22 October 2018

Nobel Prize in Medicine for discovery of cancer immunotherapy via checkpoint inhibition

By |2018-10-22T14:02:37+00:00October 22, 2018|Biomarkers, Cancer, Cancer immunotherapy, Drug Development, Drug Discovery, Haberman Associates, Immunology, Monoclonal Antibodies, Recent News, Translational Medicine|

Checkpoint inhibitor therapies (NIH)

On October 1, 2018, the The Nobel Assembly at the Karolinska Institute announced that it had awarded the 2018 Nobel Prize in Physiology or Medicine jointly to James P. Allison and Tasuku Honjo for their discovery of cancer immunotherapy via immune checkpoint inhibition.

As is usual, these Nobel Prize awards were made decades after the original discoveries. This is despite the growing importance of immunotherapy in cancer treatment, including the prospect for long-term survival of an increasing number of patients.

As we discussed in our January 9, 2014 article on this blog, the development of checkpoint inhibitors was made possible by a line of academic research on T cells that was begun in the 1980s by James P Allison, Ph.D., one of the 2018 Nobel laureates. Dr. Allison’s research focused on targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on activated T cells in tumors.

Even after Dr. Allison’s research demonstrated in 1996 that an antibody that targeted CTLA-4 had anti-tumor activity in mice, no pharmaceutical company would agree to work on this system. However, the monoclonal antibody (mAb) specialist company Medarex licensed the antibody in 1999. Bristol-Myers Squibb (BMS) acquired Medarex in 2009, and the anti-CTLA-4 mAb ipilimumab (BMS’ Yervoy) was approved in 2011 for treatment of metastatic melanoma. It was the first checkpoint inhibitor to be approved by the FDA.

Meanwhile, Dr. Honjo discovered the T-cell protein PD-1 in 1992. PD-1 (programmed cell death protein 1) acts as a brake on the immune system via a different mechanism. PD-1 became a target for other checkpoint inhibitors, notably nivolumab (BMS’ Opdivo—originally developed by Medarex and Ono Pharmaceutical) and pembrolizumab (Merck’s Keytruda). The FDA approved nivolumab for treatment of metastatic melanoma in 2014, and it approved pembrolizumab for the same indication, also in 2014.

Since 2014, clinical studies—and regulatory approvals—of checkpoint inhibitor therapies have been expanded to other types of cancer (e.g., lung and renal cancers, lymphomas). They now also include mAb agents that target yet another checkpoint protein, PD-L1. (programmed death-ligand 1).  Moreover, clinical studies of combination therapies of inhibitors of both PD-1 and CTLA-4 in patients with metastatic melanoma showed that the combination therapy is more effective than treatment with either agent alone.

Clinical studies on immune checkpoint therapy have since developed rapidly. Researchers have applied this type of therapy to a wide range of types of cancer, and have also developed additional checkpoint inhibitor drugs. A major reason for the intense interest in checkpoint inhibitor therapy is the potential of these drugs to produce long-term survival. However, only a minority of patients show such dramatic responses. Researchers have therefore been attempting to develop biomarkers and diagnostic tests to identify factors that promote long-term survival in patients. They have also been working to develop potentially more-effective therapies by combining checkpoint inhibitors with other agents. Such attempts to build on prior achievements in immuno-oncology to improve outcomes for more patients are often referred to as “immuno-oncology 2.0.” Agents that are intended to improve the results of treatment with agents like checkpoint inhibitors may also be referred to as “second-wave” or “third-wave” immuno-oncology agents.

Our 2017 report, Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes  (published by Insight Pharma Reports) focuses on immuno-oncology 2.0 strategies. This report, as well as several articles on this blog, provide updated discussions of approved and clinical stage agents in immuno-oncology (including checkpoint inhibitors and “second-wave” agents). These materials also discuss other classes of cancer immunotherapy agents, such as cancer vaccines and cellular immunotherapies.

Other early immuno-oncology researchers who did not receive the Nobel

As pointed out in the October 1 Nature News article about the Nobel Prize, there were other researchers who made seminal early discoveries in immuno-oncology who were not included in the Nobel Prize. (This usually happens.)

Gordon Freeman, an immunologist at the Dana-Farber Cancer Institute (Boston, MA), was named in the Nature News article as one of these researchers. Dr. Freeman, along with immunologists Arlene Sharpe (Harvard Medical School, Boston MA) and Lieping Chen (Yale University, New Haven, CT), studied checkpoint proteins, especially a protein that binds to PD-1 known as PD-L1. PD-L1 is the target for the approved checkpoint inhibitor mAb agents atezolizumab (Roche/ Genentech’s Tecentriq) and avelumab (Merck/Serono-Pfizer’s Bavencio). Although the CTLA-4 inhibitor ipilimumab was the first checkpoint inhibitor to be approved, it has so far been shown to work only in melanoma. However, PD-1 and PD-L1 inhibitors have been approved for the treatment of 13 different types of cancer so far. According to Dr. Freeman, his discoveries and those of his collaborators “were foundational” in the development of PD-1 and PD-L1 inhibitors.

Nevertheless, Dr. Freeman also said that Dr. Allison’s work with CTLA-4 was foundational for the development of the field of immuno-oncology, beginning when most researchers and pharmaceutical companies considered it to be scientifically premature. “Jim Allison has been a real advocate and champion of the idea of immunotherapy,” he said. “And CTLA-4 was a first success.”

All in all, Dr. Freeman says that it has been exciting to watch the immuno-oncology field develop. Not only has this development involved “an incredible amount of human creativity and energy,” but many cancer patients are doing better as the result of the entry of immuno-oncology drugs into the oncologist’s armamentarium.

Also as usual, Drs. Allison and Honjo received other prestigious awards prior to receiving the Nobel. In 2015, Dr. Allison received a Lasker prize for his work in cancer immunotherapy. (Lasker awards are commonly called the “American Nobels”). Dr. Honjo won the Kyoto Prize in basic sciences in 2016. This is a global prize awarded by the Inamori Foundation.

____________________________________________________________________________________________

As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to your company, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

5 September 2018

Alnylam’s patisiran, the first ever FDA- and European Commission-approved RNAi therapeutic

By |2018-12-03T23:50:28+00:00September 5, 2018|Drug Development, Drug Discovery, Oligonucleotide Therapeutics, Rare Diseases, RNAi|

Lipid nanoparticle structure

On August 10, 2018, Alnylam Pharmaceuticals (Cambridge, MA) announced the first-ever FDA approval of an RNAi (RNA interference) drug. The drug is Alnylam’s patisiran, which is indicated for the treatment of polyneuropathy due to transthyretin-mediated amyloidosis (ATTR). ATTR is a rare inherited, debilitating, and often fatal disease caused by mutations in the transthyretin (TTR) gene. Patisiran is trade-named “Onpattro”. The FDA approved patisiran for the treatment of polyneuropathy in adults with hereditary transthyretin-mediated amyloidosis (hATTR) in adults.

On August 30, 2018 Alnylam announced that the European Commission (EC) has granted marketing authorization for patisiran for the treatment of hATTR in adults with stage 1 or stage 2 polyneuropathy.

Shortly after Alnylam’s initial announcement, Nature published a news article in its 16 August 2018 issue, entitled “Gene-silencing technology gets first drug approval after 20-year wait”, by senior reporter Heidi Ledford, Ph.D.

As discussed in the Nature article, patisiran is the first-ever FDA approved drug based on RNA interference (RNAi), a specific gene-silencing technology. Two researchers—Andrew Fire of Stanford University School of Medicine in California and Craig Mello of the University of Massachusetts Medical School in Worcester—shared the Nobel Prize in Physiology or Medicine in 2006 for their 1998 publication of their discovery of RNAi. However, it took 20 years from the original discovery of RNAi until the first RNAi drug was approved by the FDA. The main technological issue that needed to be overcome to turn RNAi into drugs was drug delivery.

Formulation of the RNAi agent patisiran in lipid nanoparticle carriers

We discussed patisiran (then also known as ALN-TTR02) in our January 24, 2014 article on this blog. Patisiran consists of a specific oligonucleotide molecule encapsulated in a lipid nanoparticle (LNP) carrier (formerly known as a SNALP—stable nucleic acid lipid particle). The oligonucleotide is designed to inhibit expression of the gene for TTR via RNA interference. The LNP (see the Figure above) is based on technology developed by Alnylam’s partner Arbutus Biopharma (formerly known as Tekmira). LNP-encapsulated oligonucleotides accumulate in the liver, which is the site of expression, synthesis, and secretion of TTR.

The carrier used in patisiran is a second-generation LNP that contains combinations of synthetic ionizable lipid-like molecules known as lipidoids. This strategy was developed by Alnylam in collaboration with Dr. Robert Langer’s laboratory at MIT. The second-generation LNP renders patisiran much more potent than the first generation version of Alnylam’s anti-TTR product, ALN-TTR01. In a Phase 1 clinical trial (referenced in our January 24, 2014 blog article), ALN-TTR02 gave mean reductions at doses from 0.15 to 0.3 milligrams per kilogram ranging from 82.3% to 86.8% at 7 days, with reductions of 56.6 to 67.1% at 28 days.

On September 20, 2017 Arbutus announced the success of a Phase 3 clinical trial of Alnylam’s second-generation LNP-encapsulated anti-TTR agent, patisiran.

We included a detailed discussion of the development of second-generation LNP-encapsulated RNAi products, especially ALN-TTR02/patisiran, in Chapter 4 of our book-length report, RNAi Therapeutics: Second-Generation Candidates Build Momentum, published by Cambridge Healthtech Institute’s Insight Pharma Reports in October 2010.

Phase 3 clinical trial of patisiran published in the New England Journal of Medicine

The New England Journal of Medicine (NEJM) published a Phase 3 trial (known as APOLLO) of patisiran in patients with hereditary transthyretin amyloidosis (hATTR) in its July 5, 2018 issue.  According to Alnylam, the FDA approval of patisiran was based on the positive results of this trial. APOLLO was a randomized, double-blind, placebo-controlled, global Phase 3 study, and was the largest-ever study in hereditary ATTR amyloidosis patients with polyneuropathy.

The APOLLO study showed that patisiran treatment improved measures of polyneuropathy, quality of life, activities of daily living, ambulation, nutritional status and autonomic symptoms–as compared to the placebo group, in adult patients with hATTR amyloidosis with polyneuropathy. The most common adverse events in patisiran-treated patients were upper respiratory infections and infusion-related reactions. The risk of infusion-related reactions could be reduced via premedication prior to infusion.

RNAi as a premature technology, and the need to move it up the technology development curve

In our July 13, 2009 article on this blog, I mentioned the presentation that I gave earlier that year at a conference entitled “Executing on the Promise of RNAi” in Cambridge MA. My presentation was entitled, “The Therapeutic RNAi Market – Lessons from the Evolution of the Biologics Market”. In that presentation, I compared the field of monoclonal antibody (mAb) drugs to that of RNAi drugs. Despite the high level of investment in therapeutic RNAi over nearly 20 years, the formation of numerous biotech companies specializing in RNAi drug development, and the strong interest of Big Pharma in the field, there still was not one therapeutic RNAi product on the market until the August 2018 launch of patisiran. At the time of the 2009 conference—and beyond—researchers envisioned significant hurdles to the development of RNAi drugs, especially those involving systemic drug delivery. Many experts therefore believed that therapeutic RNAi was scientifically and/or technologically premature.

As of the past 15-20 years, mAbs have represented the most successful class of biologics. However, the therapeutic MAb field went through a long period of scientific prematurity, from 1975 through the mid-1990s. Several enabling technologies, developed from the mid-1980s to the mid-1990s, were necessary for the explosion of successful MAb drugs, from the mid-1990s to today. Similarly, many companies and academic laboratories have been hard at work developing enabling technologies to move the therapeutic RNAi field up the technology development curve.

As catalogued in our blog, large pharmaceutical companies that had partnered with RNAi specialty biotechs and/or were pursuing their own internal RNAi drug development, dropped our of RNAi—one by one. These included Roche, Pfizer, Merck and Novartis. This was all due to the technological prematurity of the therapeutic RNAi field, especially the issue of drug delivery.

However, as of 2018, the suite of enabling technologies behind the second-generation LNP that has been incorporated into patisiran made the successful development and approval of this drug possible. The development of these technologies and delivery platforms at Alnylam and its partners—including laboratory, preclinical and clinical studies—took place over nearly a decade prior to the approval of patisiran.

As discussed in our book-length report, Alnylam and other RNAi specialty companies have been developing suites of liver-targeting therapeutics. For example, Alnylam is developing liver-targeting RNAi therapeutics for such conditions as acute hepatic porphyrias, hemophilia, and hypercholesterolemia. These clinical-stage RNAi therapeutics utilize Alnylam’s recently-developed liver-targeting Enhanced Stabilization Chemistry (ESC)-N-acetylgalactosamine (GalNAc) delivery platform rather than the RNP delivery vehicle.

However, according to Alnylam cofounder Thomas Tuschl, Ph.D. (Rockefeller University and the Howard Hughes Medical Institute, New York, NY), as quoted in the August 2018 Nature News article, Alnylam and other RNAi specialty companies are also working on RNAi-based therapies that are designed to target organs other than the liver. For example, Quark Pharmaceuticals (Fremont, CA) is testing RNAi therapies that target the kidneys and the eye. Alnylam is developing therapies that target the central nervous system (CNS), and Arrowhead Pharmaceuticals (Pasadena, CA) is developing an inhalable RNAi therapeutic for cystic fibrosis.

Rare-disease drug development and RNAi

Recently, there has been a controversy about development of drugs for rare diseases. This has been played out between an article by Milton Packer MD (Distinguished Scholar in Cardiovascular Science, Baylor University Medical Center) on Medpage Today and one by John LaMattina, Ph.D. (Senior Partner, PureTech Health; former President of R&D, Pfizer) in Forbes.

Rare diseases (as defined by NIH) are diseases that affect fewer than 200,000 individuals. There are an estimated 7,000 rare diseases. Some of the more common of these diseases are well known: e.g., muscular dystrophy, cystic fibrosis and multiple sclerosis. Many forms of cancer can also be considered rare diseases. Although each of these diseases is “rare”, the aggregate number of rare-disease patients in the U.S. is—according to the NIH—25 million. Thus “rare-disease patients” are not rare at all.

Dr. Packer argues that:

  • the pharmaceutical industry is obsessed with rare-disease drugs;
  • the FDA is less stringent about the types of data that it requires for approval for a new rare-disease drug;
  • pharmaceutical companies have found that they can charge exorbitant prices for rare-disease drugs;
  • if a company decides to develop a new rare-disease drug, the development costs will be low compared to drugs for more common diseases, the return on investment can be enormous, and the developer will have marketing exclusivity for many years.

Dr. LaMattina counters that the first two of these statements are not true. Moreover, even though rare-disease drugs command a high price, they still may lower the cost of treatment. If a rare disease costs the healthcare system $200,000/patient/year, and a new drug for this disease both ameliorates the disease and reduces other costs for treating these patients, a price of $100,000/patient/year can be a bargain – as well as help the patient. Payers thus often accept the high prices of rare-disease drugs.

With respect to market exclusivity, all drugs—whether for rare diseases or not—get the same length of patent exclusivity. There can also be tremendous competition in rare disease R&D leading to the potential for multiple drugs (and types of drugs) to treat specific rare diseases. This competition can also drive down prices.

An important issue that was not discussed in this exchange is that rare-disease research makes possible development of totally new types of therapies that may eventually be used for more common diseases. The development of patisiran—the first ever approved RNAi therapeutic—for the rare disease ATTR is a prime example. Gene therapy also represents an entirely new suite of technologies that have been first applied to rare diseases. See, for example, the recent approval of Spark’s Luxturna (voretigene neparvovec-rzyl) for the treatment of a rare inherited retinal disease. Several CAR-T (chimeric antigen receptor-T cell) therapies have been recently developed and approved for treatment of several types of rare hematologic cancers. Other CAR-T therapies are being developed for cancers that still do not have good treatment options. Meanwhile, the first clinical trial of a treatment based on the gene-editing technology known as CRISPR-Cas9 for the rare diseases beta thalassemia and sickle cell disease has recently launched.

Thus the rare disease field has been and will continue to be a fertile area for the development and application of novel therapies. Some of these therapies may eventually be applied to more common diseases. In particular, this includes RNAi-based therapies.

____________________________________________________________________________________________

As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to your company, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

22 February 2018

JP Morgan 2018 (JPM18) panel optimistic for new breakthrough immuno-oncology therapies despite a crowded field

By |2018-09-12T21:30:29+00:00February 22, 2018|Cancer, Drug Development, Drug Discovery, Haberman Associates, Immunology, Monoclonal Antibodies, Personalized Medicine, Strategy and Consulting, Translational Medicine|

On January 12, 2018, Endpoints News sponsored a breakfast panel at the 2018 JP Morgan Healthcare Conference (JPM18) in San Francisco, CA. The focus of this panel was the current state of clinical cancer immunotherapy development. The full panel is recorded as a video on YouTube. The panel is also discussed in a special Web article on Endpoint News.

The impetus for this panel was a published research report (dated 1 January 2018) by Aiman Shalabi and his colleagues at The Anna-Maria Kellen Clinical Accelerator, Cancer Research Institute (CRI), New York, NY USA. A slide presentation based on this report [including the role of the CRI in immuno-oncology (IO) innovation] is also included at the bottom the Endpoint News special article.

The panelists in the Endpoint News program (which was entitled “How many PD-1/L1 drugs do we need? Where is immunotherapy headed?”) were Jay Bradner (Novartis Institutes for BioMedical Research) Hervé Hoppenot (Incyte), Ellen Sigal ( Friends of Cancer Research), David Berman (AstraZeneca), Gideon Blumenthal (FDA Office of Hematology and Oncology Products), and Aiman Shalabi. The moderator of the panel was John Carroll, the Co-founder and Editor of Endpoints News.

The major conclusion of the published research report and of the panel discussion was that anti-PD-1/PD-L1 studies (including studies of combinations of anti-PD-1/PD-L1 therapies with other agents) will continue to deliver many breakthroughs, with the strong potential to change the standard of care for many types of cancer. However, there is an urgent need for efficiencies. Specifically, a large number of companies and academic groups are testing the same combinations, often using inefficient trial designs. In particular, there has been a great increase in the number of small, investigator-initiated studies.

The CRI team discussed some initiatives aimed at addressing these challenges. In particular, there is the need to move toward novel, collaborative trial designs that allow more questions to be answered more efficiently in a single multicenter trial. Many biotechnology and pharmaceutical companies are adopting these types of study designs. (For example, see Merck’s KEYNOTE-001 adaptive trial of pembolizumab/Keytruda, which led to accelerated approval for metastatic melanoma and NSCLC, as well as a companion diagnostic.) However, such clinical studies sponsored by a single company tend to include drugs only from their own portfolio.

The nonprofit and public sectors, however, can facilitate and conduct these innovative trials across multiple companies and research centers. There are now several examples of nonprofit organizations leading such novel study designs. One example, which was discussed in the Endpoint News panel, is the LUNG-MAP study for lung cancer. LUNG-MAP is a collaboration between Friends of Cancer Research, Foundation for NIH, National Cancer Institute, the Southwest Oncology group, and various biopharmaceutical and diagnostic companies. (Panelist Ellen Sigal of Friends of Cancer Research was especially active in discussing LUNG-MAP.) The study is now open with multiple arms at hundreds of sites.

Dr. Shalabi and his colleagues conclude that now—with the strong emergence of IO therapies—is probably the best time for progress in oncology in several decades. This historic opportunity would be maximally capitalized if people from academia, industry, regulatory agencies, and nonprofit organizations work together, especially in adopting novel collaborative study design, aimed at bringing the promise of cancer immunotherapies to patients, sooner rather than later.

Are there enough patients for IO clinical trials in 2018?

One factor that is often cited as severely limiting the ability of researchers to conduct all the clinical trials in progress and planned for IO agents and combinations is a shortage of patients. The panelists cited a number of 52,000 patients now in trials, with many more needed. However, the panelists estimated that there are 2 million patients per year that are dying of cancer. The best chance for these patients’ survival is for them to be enrolled in a clinical trial, often an IO trial. However, most cancer patients are treated in community settings, and are not even offered clinical trials—let alone the clinical trials that would be the most appropriate for each patient’s disease. From the point of view of patients, their caregivers, and of the research community, these patients need access to clinical trials.

Several panelists (notably Jay Bradner of Novartis) cited the need to move toward patient-driven IO clinical research, and to enlist the patient as a collaborator in clinical trials (for example, via conducting on-treatment tumor biopsies). In support of moving towards patient-driven IO clinical research, the CRI website includes a “Patients” page, that links to a “clinical trial finder”. In our own Biopharmconsortium Blog, the January 12, 2015 article included a section entitled “Implications for patients with terminal cancers”. That section featured links to CRI web pages on immunotherapy trials for pancreatic cancer and glioblastoma, which we used as examples of deadly cancers that have become the subject of IO clinical trials. Now—in 2018—it is even more imperative that IO trials become patient-driven.

Why so many IO combination clinical trials?

Many of the IO trials currently in progress are combination trials with a checkpoint inhibitor and a second agent. The rationale for these trials is that there is a significant unmet need in IO, since (depending on the type of cancer) some 80% of patients do not respond to checkpoint inhibitors. As we discussed at length in our 2017 book-length report, “Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes”, and more briefly in our September 20, 2017 article on this blog, checkpoint inhibitors work by reactivating intratumoral T cells, especially CD8+ cytotoxic T cells. Checkpoint inhibitors are therefore ineffective in treating “cold” tumors (which lack T cell infiltration), and immunosuppressed tumors that inhibit infiltrating T cells. Researchers and companies are therefore attempting to develop agents that render cold or immunosuppressed tumors “hot”. When such agents are given in combination with checkpoint inhibitors, they may improve their effectiveness, thus resulting in tumor shrinkage. This type of strategy, as discussed in our report, is a major theme of “second wave” immuno-oncology, or “immuno-oncology 2.0.” Many of these agents are discussed in our 2017 report.

Many of these complementary “immunotherapy 2.0” agents are being developed by small or medium-sized biotechnology companies. (One such medium-sized company, Incyte, was represented on the JPM18 panel.) Large pharmaceutical companies that have been developing checkpoint inhibitors are thus seeking to collaborate with or acquire smaller companies that are developing “immunotherapy 2.0” agents. Interestingly, Jay Bradner of Novartis stated that he was more concerned about competition from the “500 biotechs within a 20 mile radius around Novartis Institutes for BioMedical Research (NIBR)-Cambridge” than from another Big Pharma in IO. However, in terms of conducting clinical trials, Novartis has a big advantage over small biotechs because of its global reach—it can expand a clinical trial by opening up sites in Europe. Nevertheless, NIBR-Cambridge is actively recruiting the participation of biotech companies in IO combination studies, and wishes to become the “partner of choice” for such collaborative studies.

The JPM18 panel is optimistic for the prospects of IO therapies

The JPM18 panel was very optimistic that IO clinical studies will result in breakthrough therapies that will change the practice of treatment of important types of cancer, and that such breakthroughs should start to emerge within the next two years.

This is in contrast to the pessimism of many people in the biotech/pharma industry, and in parts of the venture capital community. For example, a January 4, 2018 article in Forbes by venture capitalist Bruce Booth suggests that the crowding of the IO field is making it difficult for small biotechs to compete with the clinical and post-marketing programs of the larger companies, and that starting new IO companies is difficult. Researchers, entrepreneurs and funders would be better off focusing on areas like neuroscience, according to this article.

Nevertheless:

1. Potentially important IO deals between small and large companies are being done. For example, on February 14, 2018 Nektar Therapeutics (San Francisco, CA) and Bristol-Myers Squibb (BMS) announced that they had concluded a $3.6 billion collaboration deal for a minority share of Nektar’s early-stage T-cell modulator NKTR-214, a CD122 agonist. The collaboration will study combinations of NKTR-214 with BMS’ checkpoint inhibitors Opdivo and Yervoy, in 20 indications involving 9 types of tumors. We covered NKTR-214 in the chapter on immune agonists in our 2017 Cancer Immunotherapy report.The Opdivo/NKTR-214 combination has been evaluated in Phase 1/2 studies. Nektar and BMS now are initiating clinical trials with the potential for registration data that could start coming in in about 18 to 24 months.

2. New IO companies are being started and funded. Tmunity Therapeutics, a CAR-T based cellular immunotherapy company, was founded by Carl H. June, MD and his collaborators at Penn Medicine in January 2016. On January 23, 2018, Tmunity announced that it was raising $100 million from a group of investors including Gilead Sciences, the Parker Institute for Cancer Immunotherapy, Ping An Ventures, and Be The Match, a patient advocacy group. The company will use the funding in part to finance two clinical trials that will attempt to use genetically modified T-cells to treat solid tumors. As we discussed in our 2017 Cancer Immunotherapy report, using CAR-T and related types of T cells to treat solid tumors has proven to be more difficult than treating blood cancers. Tmumity researchers are attempting to overcome these difficulties.

Meanwhile, CAR-T company Juno Therapeutics (Summit, NJ) is being acquired by Celgene for approximately $9 billion.

3. Researchers continue to make discoveries with the potential to improve the efficacy and safety of IO therapies for increasing numbers of patients. For example, the February 2018 issue of Nature Biotechnology reported on two such discoveries: a model to determine which tumor neoepitopes (or neoantigens) are likely to result in tumor response to checkpoint inhibitor therapy, and studies on the effects of gut bacteria on patent response to IO treatments. The tumor neoepitope research was originally published in the 22 November 2017 issue of Nature . We discussed neoantigen modeling and other aspects of neoantigen science in three types of IO therapies (checkpoint inhibitor, cancer vaccine, and cellular immunotherapy) in our 2017 Cancer Immunotherapy report.

The gut bacteria/tumor IO research was originally published in the 2 November 2017 issue of Science, and was reviewed in a News article in Nature.

A third recent discovery concerns the role of TGF-beta in resistance to checkpoint inhibitor therapy. In mouse models, a TGF-beta inhibitor enables T cells to get into IO resistant tumors. Checkpoint inhibitor therapy (given together with the checkpoint inhibitor) then becomes more effective in shrinking the tumor. Several TGF-beta inhibitor/checkpoint inhibitor combinations are now in clinical studies. However, to date, TGF-beta inhibitors have been suffering from various safety and/or efficacy issues.Therefore, some researchers have suggested the need for developing improved TGF-beta pathway inhibitors for use in combination with checkpoint inhibitors.

As research on IO continues, some of these discoveries will make their way into improved therapies with increased patient benefit.

Our report, “Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes”

Our 2017 Cancer Immunotherapy report can help you achieve a deep understanding of the IO field. This especially applies to immuno-oncology 2.0, which is the basis for IO combination trials. Our report covers the three major areas of IO R&D—checkpoint inhibitor therapy (including combination therapies), cancer vaccines, and cellular immunotherapies. Immunotherapy 2.0 strategies, agents, and companies discussed in our report may well make the news over the next several years, in terms of corporate deals and product approvals. This has already been happening, as illustrated by the BMS/Nektar collaboration discussed earlier, the emergence of strategies and clinical trials aimed at developing CAR-T therapies for solid tumors at Tmunity, and the continuing development of neoantigen science aimed at improved IO therapies. Our report is thus well worth purchasing and reading for those who are interested in the further development of IO.

For more information on our report, Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes, or to order it, see the CHI Insight Pharma Reports website.

As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to your company, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

7 December 2017

”Improving Candidate Selection: Translating Molecules into Medicines.”

By |2018-09-12T21:41:42+00:00December 7, 2017|Cancer, Drug Development, Drug Discovery, Gene Therapy, Haberman Associates, Immunology, Monoclonal Antibodies, Oligonucleotide Therapeutics, Recent News, RNAi, Strategy and Consulting|

Bromodomain. A chromatin “reader” that is a target of PPI drug development. Source: WillowW at the English language Wikipedia.

 

Allan B. Haberman, Ph.D. was one of about 25 experts from pharmaceutical, biotechnology, and consulting firms who attended Aptuit’s  one-day think-tank event, ”Improving Candidate Selection: Translating Molecules into Medicines”. This was the third and final such networking and discussion symposium, which was held in downtown Boston, on December 4, 2017. The previous two events in this series had been held in San Francisco (18th & 19th Sept 2017) and in Hertfordshire, UK (22nd & 23rd Oct 2017). The Boston discussion session was preceded by a relaxed networking dinner on the evening of the 3rd.

Attendees and presenters at the Boston meeting were from Shire, Celgene, Forma Therapeutics, Roche, Amgen, Novartis, the Broad Institute, Warp Drive Bio, Mass General Hospital, EnBiotix, Yumanity, and Ra Pharma—among others—as well as from Aptuit and its parent company Evotec.

The focus of the meeting was on improving drug candidate selection in order to improve development success. Only about 10% of drug candidates make their way from first-in-humans trials to regulatory approval. The greatest amount of attrition occurs in Phase 2. Approximately half of candidates fail at that stage, mainly due to lack of efficacy.

One of the key issues discussed in the symposium was the role of the Lipinski Rule of Five—a set of physico-chemical properties that determine the “drug-likeness” of a clinical candidate; i.e., whether a compound is likely to be an orally active drug in humans. Some participants stated that these guidelines had been interpreted too rigidly, and have excluded many potentially good drugs from further development. They stated that the Lipinski rules are only guidelines, and do not replace thinking. (For a similar point of view, see Paul Leeson’s 2012 News and Views article in Nature.) For example, researchers should measure physical properties empirically, rather than inferring them.

The Lipinski rules also exclude whole classes of drug candidates—such as natural products and macrocyclic compounds—from consideration. Before the era of combinatorial chemistry and high-throughput screening, natural products were the mainstay of drug discovery and development.

The Haberman Associates website contains reports, articles, and links to reports that are useful in understanding the issues discussed in the Aptuit symposia. Links to most of these publications can be found on our Publications page. Notably, there is a 2009 report entitled Approaches to Reducing Phase II Attrition, which is available from Insight Pharma Reports. There is also a 2009 article (available on our website at no cost) based on that report, entitled “Overcoming Phase II Attrition Problem.”

Drug attrition numbers have not changed since our 2009 publications. However even back in 2009, pharmaceutical company researchers attributed high attrition rates due to lack of efficacy to companies’ addressing more complex diseases, with the need to discover and develop drugs that have novel mechanisms of action and/or address unprecedented targets. At the December 4 Aptiut symposium, participants similarly attributed high attrition rates to researchers’ tackling new classes of drugs. These included drug classes whose development involves working with premature technologies—e.g., protein-protein interactions (PPIs), gene therapy, RNAi, CAR-T therapies, cancer vaccines, , and combination immuno-oncology therapies.

Working on development of drugs based on premature technologies involves development of enabling technologies that will allow researchers to “move up the technology development curve” and thus to achieve increasing success in drug development. R&D in some of these fields—notably development of checkpoint inhibitors for use in immuno-oncology—has been moving up the technology curve, resulting in notable successes.

Although attrition rates have not changed since 2009, drug developers have been working with increasingly newer classes of drugs. Attrition thus continues to be a moving target.

Among the publications available on our website is our 2012 report—Advances in the Discovery of Protein-Protein Interaction Modulators. As the result of corporate restructuring, this report has not be available anywhere in recent years. However, with the permission of the publisher, Datamonitor Healthcare (a division of Informa), we are now hosting it on our website.

Aptuit’s “Translating molecules into medicines” symposia and improving drug discovery and development

The purpose of Aptuit’s symposia was “to discuss and learn from the experiences of those involved in working at the interface of discovery and development. These meetings were designed to give attendees the chance to build meaningful relationships, challenge their understanding of certain subjects and learn from leading members of their peer group in a non-commercialized setting.”

The organizers of the symposia ask whether “having the flexibility to think beyond established rules and adopting more collaborative development strategies will be just as important as the innovative science and technologies for drug discovery and development.” We at Haberman Associates look forward to assisting you in your efforts to move your drug discovery and development programs forward.

As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to your company, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

19 October 2017

Can immunotherapy 2.0 strategies save the cancer vaccine field?

By |2018-09-12T21:30:39+00:00October 19, 2017|Cancer, Drug Development, Drug Discovery, Haberman Associates, Immunology, Monoclonal Antibodies, Personalized Medicine, Recent News, Strategy and Consulting, Translational Medicine|

CTLs attacking cancer cells.

 

On September 15, 2017, Bavarian Nordic’s Phase 3 trial of its cancer vaccine Prostvac ended in failure. Prostvac failed to improve overall survival in patients with metastatic castration-resistant prostate cancer, as determined by the clinical trial.

We had listed Prostvac in Chapter 5 and in Table 5-2 of our 2017 report, Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes, as a cancer vaccine that was in Phase 3 clinical trials. However, as we stated in that chapter, “It is possible that one or more of the experimental agents listed in Table 5-2 may [also] experience late-stage failure.” That is because the cancer vaccine field has been subject to a high rate of clinical failure, including several late-stage failures in 2016.

Despite the high rate of failure in the cancer vaccine field, there are now two FDA approved cancer vaccines— sipuleucel-T (Dendreon/Valeant’s Provenge) and talimogene laherparepvec (Amgen’s Imlygic/T-Vec), the latter of which is an oncolytic virus, rather than a true cancer vaccine. However, both of these agents are rather marginal therapies. Sipuleucel-T has an apparently minimal effect and is very expensive and difficult to manufacture. T-Vec must be injected directly into a tumor, and as a monotherapy, there is no evidence for improvement of overall survival or effects on distant metastases. However, researchers have hypothesized that as a directly-injected agent, T-Vec might produce an inflammatory tumor microenvironment that will provide an ideal target for checkpoint inhibitors. Thus, researchers have had expectations that combination therapies of T-Vec with checkpoint inhibitors which are now in progress may yield much better results.

Indeed, on October 6, 2017, a peer-reviewed Phase 2 published study indicates that a combination of Imlygic and Bristol-Myers Squibb’s (BMS’) CTLA4 checkpoint inhibitor Ipilimumab (Yervoy) doubles response rates in advanced melanoma as compared to Yervoy alone. The published trial results show that the objective response rate for the combination was 39%, compared to 18% for Yervoy alone. With respect to complete responses, the combination gave13% as compared to 7% for Yervoy alone. Responses occurred in patients with and without visceral disease and in uninjected lesions after combination treatment, according to the study.

Amgen’s head of R&D, Sean E. Harper MD says that the trial provides an important proof-of-concept for combining the complementary mechanisms of an oncolytic viral immunotherapy and a checkpoint inhibitor to enhance antitumor effects, adding that the company intends to test Imlygic in combination other checkpoint inhibitors in “a variety of tumor types”.

Imlygic—in combination with another checkpoint inhibitor, pembrolizumab (Merck’s PD-1 inhibitor Keytruda)—is in a Phase 3 trial (KEYNOTE-034, clinical trial number NCT02263508) in advanced melanoma. This trial is expected to yield preliminary results in 2018. In 2014, the Phase 1b/2 MASTERKEY-256 trial of the Imlygic/Keytruda combination in advanced melanoma showed an overall response rate (ORR) of around 56%.

These data indicate that the immunotherapy 2.0 strategy of using Imlygic to generate an inflammatory tumor microenvironment may produce a synergistic clinical effect and enhanced anti-tumor immune response in patients with metastatic melanoma who are also treated with a checkpoint inhibitor.

As we discuss in Chapter 5 of our 2017 Cancer Immunotherapy report, several cancer vaccine developers are pursuing a similar strategy—use cancer vaccines to render tumors inflamed [i.e. especially with cytotoxic tumor-infiltrating lymphocytes (TILs)], and use checkpoint inhibitors to induce regression of the inflamed tumors. In some cases, cancer vaccines are being tested in combination with checkpoint inhibitors in Phase 1 or Phase 2 clinical trials, rather than the “traditional” approach of first getting a vaccine approved and then conducting trials of the vaccine in combination with other agents. The hope is that testing a vaccine in combination with a checkpoint inhibitor in early stage clinical trials might prevent clinical failure of a potentially useful cancer vaccine. However, whether this strategy will work for any particular vaccine remains to be seen.

Neoantigen cancer vaccines

Another novel immunotherapy 2.0 strategy for cancer vaccine discovery and development discussed in our report involves neoantigen science. Recent studies exploring mechanisms by which TILs and other components of the immune system recognize tumor cells and differentiate them from noncancer cells have focused on “neoantigens”—i.e. antigens that are specific for cancer cells as opposed to normal, noncancer cells. These neoantigens are associated with somatic mutations that arise in the evolution of tumor cells. Neoantigen-specific TILs appear to mediate tumor regression, and this antitumor activity may be enhanced by checkpoint inhibitor therapy. Such studies have led researchers to hypothesize that personalized neoantigen-based vaccines may be more effective than earlier types of cancer vaccines. Some researchers have therefore been attempting to develop technology platforms for vaccine design based on determination of neoantigens in tumors.

In particular, neoantigen researchers at the Dana-Farber Cancer Institute, the Broad Institute, Massachusetts General Hospital, and Brigham and Women’s Hospital recently founded a company, Neon Therapeutics (Cambridge, MA). Neon focuses on neoantigen science and technology for the development of neoantigen-based therapeutic vaccines and T-cell therapies to treat cancer.

These researchers published a report in the 13 July issue of Nature describing their Phase 1 study in patients with previously untreated high-risk melanoma of a personalized neoantigen vaccine designated NEO-PV-01 by Neon Therapeutics and in Chapter 5 of our report.

As discussed in our report, Neon’s lead clinical program, NEO-PV-01, builds upon initial clinical trials developed collaboratively by the Broad Institute and the Dana-Farber. NEO-PV-01 is a personalized vaccine that is custom-designed and manufactured to include targets for the immune system [i.e. naturally-processed, major histocompatibility complex (MHC)-binding, neoantigen peptide epitopes] that are unique to an individual’s cancer. The 13 July Nature report focuses on results of the ongoing Phase 1 clinical trial designated NCT01970358 of the combination of poly-ICLC [poly-inosinic acid/poly-cytidylic acid/poly-lysine, an adjuvant] and multiple neoantigen peptide epitopes in melanoma.

As discussed in that Nature paper, neoantigens were long envisioned as optimal targets for anti-tumor immune responses. However, the systematic identification of neoantigens in a particular patient’s tumors only became feasible with the availability of massively parallel sequencing for detection of coding mutations, and of machine learning technology to reliably predict those naturally-processed mutated peptides that bind with high affinity to autologous major histocompatibility (MHC) molecules. (The term “naturally-processed” refers to antigenic peptide epitopes that are processed intracellularly and which bind with high affinity to autologous class I or class II MHC molecules. The MHC/peptide complexes are then recognized by T cells.)

In the study described in the 13 July Nature paper, the researchers demonstrated the feasibility, safety, and immunogenicity of a vaccine (designated NEO-PV-01 as discussed earlier), which targets up to 20 predicted personal tumor neoantigens. Vaccine-induced polyfunctional CD4+ and CD8+ T cells targeted 58 (60%) and 15 (16%) of 97 unique neoantigens across patients, respectively. These T cells discriminated mutated from wild-type antigens, and in some cases directly recognized autologous tumor. Of six vaccinated patients, four had no recurrence as of 25 months post-vaccination. Two other patients who had recurrent disease were subsequently treated with the anti-PD-1 antibody pembrolizumab (Merck’s Keytruda). These two patients experienced complete tumor regression, with expansion of the repertoire of neoantigen-specific T cells.

These results strongly support further development of the researchers’ neoantigen vaccine approach, both alone and in combination with checkpoint inhibitors or other immunotherapies. Neon Therapeutics is currently sponsoring an open-label Phase 1b clinical study of NEO-PV-01 plus adjuvant in combination with nivolumab (BMS’ Opdivo) in patients with melanoma, smoking-associated non-small cell lung carcinoma (NSCLC) or transitional cell bladder carcinoma (clinical trial number NCT02897765). Neon entered into a collaboration with BMS to perform this clinical trial in late 2015.

Neon is also developing NEO-PTC-01, a personal neoantigen autologous T cell therapy, which is now in the research and process development stage. As discussed in Chapter 6 of our 2017 cancer immunotherapy report, neoantigen science is also a factor in adoptive cellular immunotherapy for cancer, especially in Steven A. Rosenberg MD, PhD’s recent studies of TIL therapy.

Other neoantigen cancer vaccine companies

In addition to Neon, other young companies that specialize in development of neoantigen-based cancer vaccines include BioNTech AG (Mainz, Germany), Gritstone Oncology (Emeryville, CA and Cambridge, MA), ISA Pharmaceuticals (Leiden, The Netherlands), Agenus (Lexington, MA), and Caperna (Cambridge, MA). Of these companies, BioNTech and Caperna [which is a Moderna (Cambridge, MA) venture company] are developing RNA-based personalized neoantigen vaccines. The other companies are developing peptide neoantigen vaccines based on their proprietary technologies.

Conclusions

As discussed in this article, and in our 2017 report, Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes, researchers and developers are applying several immunotherapy 2.0 approaches to attempt to reverse the high rate of failure in the cancer vaccine field.

Moreover, neoantigen science has a potentially wide field of application, ranging from improving clinical outcomes of treatments with checkpoint inhibitors to development of more effective cancer vaccines and of novel cellular immunotherapies.

Our report contains materials designed to enable readers to understand complex issues in neoantigen science, and especially to understand applications of neoantigen science in research reports, clinical trials, corporate news, and product development.

For more information on our report, Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes, or to order it, see the CHI Insight Pharma Reports website.

As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to your company, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.