Biopharmconsortium Blog

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.

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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 |2018-09-11T21:46:52+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.

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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.

23 August 2018

NewLink Genetics—new organizational and clinical trial strategy for development of its cancer immunotherapy drug indoximod

By |2018-09-12T21:30:40+00:00August 23, 2018|Cancer, Cancer immunotherapy, Drug Development, Immunology, Translational Medicine|

Indoximod (1-methyl-D-tryptophan)

In Chapter 2 of our 2017 book-length report, Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes (published by Insight Pharma Reports), we discussed the major approved and emerging checkpoint inhibitors and checkpoint inhibitor modulators. Most of these, exemplified by the PD-1 inhibitors pembrolizumab (Merck’s Keytruda) and nivolumab (BMS’ Opdivo), and the PD-L1 inhibitor atezolizumab (Roche/ Genentech’s Tecentriq), are monoclonal antibodies (mAbs). Chapter 2 also included discussions of several small-molecule checkpoint inhibitor modulators, notably NewLink Genetics’ indoximod (D-1-methyl-tryptophan). Indoximod is an inhibitor of tryptophan catabolism via the kynurenine pathway (also known as the IDO pathway). IDO1 (indoleamine 2,3-dioxygenase 1) is the enzyme that catalyzes the first and rate-limiting step of that pathway.

We also discussed NewLink’s IDO pathway programs in the November 25, 2014 article on this blog.

Recently, on July 31, 2018, NewLink announced that it has decided to focus its indoximod clinical programs on treatment of three specific indications:

  1. recurrent pediatric brain tumors,
  2. front-line treatment of diffuse intrinsic pontine glioma (DIPG),
  3. front-line treatment of acute myeloid leukemia (AML).

These are relatively rare cancer indication with high unmet medical need. NewLink will also continue to advance NLG802, a prodrug of indoximod. NLG802 has demonstrated significantly higher pharmacokinetic exposure in preclinical models.

This program is in contrast to NewLink’s previous clinical trial focus on advanced metastatic melanoma, a more “mainstream” target for cancer immunotherapy. Specifically, the company had been conducting Phase 1/2 studies of combinations of indoximod with the leading checkpoint inhibitors pembrolizumab (Merck’s Keytruda) or nivolumab (Bristol-Myers Squibb’s Opdivo). On April 16, 2018, NewLink announced that it would not proceed to the randomization portion of these Phase 1/2 studies.

NewLink’s change in its clinical trial strategy, as well as its organizational and financial restructuring, was in reaction to the recent Phase 3 failure of Incyte’s IDO-inhibitor drug epacadostat (in combination with pembrolizumab), in late-stage melanoma.

At the time of NewLink’s initial announcement of its change in clinical trial strategy (April 18, 2018), the company’s shares were down 8% premarket. This was despite the simultaneous release of positive preliminary Phase 1 data on the effect of indoximod treatment of children with progressive brain tumors.

Organizational changes in support of NewLink’s new strategy

NewLink has completed a set of organizational changes designed to support its new strategy within its current financial capacity, to substantially cut future expenses, and to extend its cash runway into the second half of 2021. The company is reducing its headcount by approximately 30%, and has made several changes to its senior management, in support of its strategic realignment.

As a result of its organizational changes, NewLink anticipates its current cash runway to extend into the second half of 2021. This excludes any additional financings, proceeds from strategic alliances, and other receipts or expenditures. NewLink expects to expend approximately $10 million per quarter after completing its restructuring.

Mechanistic difference between epacadostat and indoximod

As we discussed in our November 25, 2104 blog post, IDO [and the related enzyme tryptophan-2,3-dioxygenase (TDO)] are enzymes that catalyze the first and rate-limiting step of tryptophan catabolism through the IDO pathway. The resulting depletion of tryptophan, an essential amino acid, inhibits T-cell proliferation. Moreover, the tryptophan metabolite kynurenine can induce development of immunosuppressive regulatory T cells (Tregs), as well as causing apoptosis of effector T cells, especially Th1 cells.

The IDO pathway is active in many types of cancer both within tumor cells and within antigen presenting cells (APCs) in tumor draining lymph nodes. This pathway can suppress T-cell activation within tumors, and also promote peripheral tolerance to tumor associated antigens. Via both of these mechanisms, the IDO pathway may enable the survival, growth, invasion and metastasis of malignant cells by preventing their recognition and destruction by the immune system. Inhibitors of the IDO pathway may therefore block these immunosuppressive pathways, and may therefore enhance the efficacy of checkpoint inhibitor drugs. Development of IDO pathway inhibitors thus constitute an immunotherapy 2.0 strategy.

Epacadostat, Incyte’s drug candidate that failed in the Phase 3 clinical trial, is a direct inhibitor of IDO1.

In contrast, D-1-methyl-tryptophan (NewLink’s indoximod) does not inhibit IDO at all, but inhibits the IDO-related enzyme IDO2.  Indoximod also works to reverse the IDO-mediated inhibition of the immunoregulatory kinase mTOR (mammalian target of rapamycin), and specifically of mammalian target of rapamycin complex 1 (mTORC1), a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis.  mTORC1 appears to interpret indoximod as a highly potent mimetic of the amino acid L-tryptophan. It thus can reverse the effects of tryptophan catabolism mediated by the IDO pathway. It is possible that indoximod may be active against tumors driven by any tryptophan catabolic pathway. Indoximod’s unique and complex mechanism of action is not fully understood. Further investigations could thus result in new therapeutic insights. However, current results of mechanistic studies indicate the possibility that indoximod may be a superior agent to epacadostat in potentiating immunotherapeutic efficacy of checkpoint inhibitors.

Moreover, early Phase 2 clinical data on treatment of advanced melanoma patients with a combination of indoximod and the PD-1 inhibitor pembrolizumab indicated that after a median follow-up of 10.5 months, 60 evaluable patients experienced an overall response rate (ORR) of 52%, including six complete and 25 partial responses. The combination therapy was well tolerated.

However, as we discussed earlier, NewLink has shifted its clinical trial program away from melanoma to three rarer cancer indications with high unmet medical need. The outcome of the company’s efforts to develop indoximod awaits the results of the clinical trials in these cancer indications, which are now in the Phase 1b stage.

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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.

14 March 2018

MIT study finds that the probability of clinical trial success is nearly 40% higher than previously thought

By |2018-09-12T21:41:44+00:00March 14, 2018|Biomarkers, Cancer, Drug Development, Haberman Associates, Immunology, Personalized Medicine, Recent News, Strategy and Consulting, Translational Medicine|

NIH Clinical Center

On December 7, 2017 we published an article on this blog entitled ”Improving Candidate Selection: Translating Molecules into Medicines”. This article was based on a December 4, 2017 symposium sponsored by Aptuit entitled “Improving Candidate Selection: Translating Molecules into Medicines”. The focus of the meeting was on improving drug candidate selection in order to improve development success.

Our article stated that “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.” As we also stated in that article, drug attrition numbers have not changed since our 2009 publications, “Approaches to Reducing Phase II Attrition” and “Overcoming Phase II Attrition Problem”.

However, especially since the year 2000, drug developers have been working with increasingly newer classes of drugs. They attribute continuing high attrition rates to difficulties in working with ever-changing classes of drugs designed to treat complex diseases. Attrition thus continues to be a moving target.

Several more recent estimates of clinical trial success are comparable to those cited by participants in the Aptuit symposium, and in our own 2009 publications. For example, as pointed out by Endpoints News, BIO (the Biotechnology Innovation Organization) in a recent publication analyzing clinical development success rate from 2006 to 2015, determined that the overall likelihood of approval from Phase 1 for all drug candidates was 9.6%, and 11.9% for all indications other than cancer. (The likelihood of approval for oncology candidates was 5.1%; this is about the same as the figure for oncology success cited in our 2009 report.) Meanwhile, AstraZeneca cited a 5% success rate for its own candidates in a January 2018 analysis.

Now comes a January 2018 study by Andrew W Lo, Ph.D. and his colleagues at MIT that concludes that 13.8% of all drug development programs eventually lead to approval. This study was discussed in a February 1, 2018 article in Endpoints News by John Carroll. Dr. Lo is the Director of the MIT Laboratory for Financial Engineering.

As with earlier studies, the success rates depend on the particular indication. For example, infectious disease vaccines have the highest rate of success, 33.4%. Oncology drugs—as in most such studies—have the lowest rate of success—3.4%.

Dr. Lo’s study represents a Big Data approach to determining drug development success rates.The MIT group analyzed a large dataset of over 40,000 entries from nearly 186,000 clinical trials of over 21,000 compounds. To analyze this dataset, the researchers developed automated algorithms designed to trace each drug development path and compute probability of success (POS) statistics in a matter of hours. If generating POS estimates had been done by traditional manual methods, it would have taken months or years.

Despite the intense focus of the biopharmaceutical industry, investors, and the general public on cancer, the POS for oncology drugs has been consistently abysmal for years—as shown by our 2009 report, the 2016 BIO report, and the Lo et al. 2018 MIT study. However, according to the MIT study, although the POS for oncology drugs had the lowest overall approval rate of 3.4% in 2013, it rose to 8.3% in 2015. Both Dr. Lo’s group and John Carroll of Endpoint News attribute this sharp rise to the advent of immuno-oncology drugs.

As we discussed in our February 22, 2018 blog article, “JP Morgan 2018 (JPM18) panel optimistic for new breakthrough immuno-oncology therapies despite a crowded field”, leading researchers in academia and industry believe that because of the strong emergence of immuno-oncology therapies, now is probably the best time for progress in oncology in several decades. This is consistent with the findings of Dr. Lo’s group. However, as we stated in our previous blog article (based on the conclusions of the JPM18 panel), “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.”

Another issue discussed by Dr. Lo and his colleagues in their study is role of biomarkers in the success of clinical trials. The researchers compared POS estimates for trials that stratified patients using biomarkers to those that did not use biomarkers. They found that trials that utilized biomarkers tended to be more successful (by nearly a factor of 2) than those that did not. However, biomarker-stratified trials studied by the MIT group were nearly all in oncology. Therefore, it was not possible for the MIT researchers to obtain valid conclusions on the role of biomarkers for therapeutic areas outside of oncology.

Nevertheless, with the continuing development of oncology biomarkers, coupled with breakthrough R&D results in immuno-oncology, the MIT researchers expect that the rates of approval of cancer drugs will continue to improve.

Conclusions

Dr. Lo’s group intends to provide continuing information on the success rates of clinical trials, beyond this initial study. The goal is to provide greater risk transparency to drug developers, investors, policymakers, physicians, and patients, order to assist them in their decisions.

Moreover, our book-length report, Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes can help you understand the role of advances in immuno-oncology in the current and expected increases in drug development success in the cancer field.

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.