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.

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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.

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CAR T cells attacking a cancer cell. (Source: National Cancer Institute)

On May 3, 2017 Cambridge Healthtech Institute’s (CHI’s) Insight Pharma Reports announced the publication of a new book-length report, Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes, by Allan B. Haberman, Ph.D.

The new 2017 report includes an updated discussion of approved and clinical stage agents in immuno-oncology. It also addresses the means by which researchers and companies are attempting to build on prior achievements in immuno-oncology to achieve improved outcomes for more patients. This approach is often referred to as “immuno-oncology 2.0.” The American Society of Clinical Oncology (ASCO) named “immunotherapy 2.0” as its “Advance of the Year” for 2017.

As discussed in the report, researchers have found that checkpoint inhibitors such as pembrolizumab (Merck’s Keytruda) and nivolumab (Bristol-Myers Squibb’s Opdivo) produce tumor responses by reactivating TILs (tumor infiltrating lymphocytes). As a result, they have been developing biomarkers that distinguish inflamed (i.e. TIL-containing) tumors—which are susceptible to checkpoint inhibitor therapy—from “cold” tumors, which are not. They have also been working to develop means to render “cold” tumors inflamed, via treatment with various conventional therapies and/or development of novel agents. These studies constitute the major theme of immuno-oncology 2.0.

Meanwhile, cellular immunotherapy has also been advancing, with two chimeric antigen receptor (CAR) T-cell therapies (from Novartis and Kite Pharma) in preregistration with the FDA as of March 2017.

These and other areas of current cancer immunotherapy R&D are discussed in the new report.

The first wave of immuno-oncology 2.0 treatments has begun to achieve regulatory approval:

• On May 12, 2017, Merck gained FDA approval to market a combination of pembrolizumab with chemotherapy (specifically, carboplatin plus pemetrexed) for first-line treatment of non-small cell lung cancer (NSCLC). This is based on a Phase 2 clinical study that showed that the chemo/pembrolizumab combination resulted in a much higher statistically-significant overall response than chemo alone — 55% vs. 29%. As we discuss in our report, certain types of chemotherapy can induce immune responses that convert “cold” tumors into inflamed tumors, thus making them susceptible to checkpoint inhibitor treatment.
• On May 23, 2017, the FDA awarded accelerated approval to Merck’s pembrolizumab for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that exhibit high microsatellite instability (MSI-H) or are mismatch repair deficient (dMMR). This indication includes patients with solid tumors that have progressed following prior treatment, and who have no satisfactory alternative treatment options. It also includes patients with colorectal cancer that has progressed following treatment with chemotherapy. This is the first approval of an anticancer agent based on a tumor’s biomarker, regardless of where the tumor originated in the body. As we discuss in our report, mismatch-repair deficiency results in a large somatic mutation load. This supports a large and diverse population of TILs, which are specific for mutation-associated neoantigens. Treatment with checkpoint inhibitors may reactivate these TILs, resulting in effective antitumor immune responses.

Our report is designed to enable readers to understand current and future developments in immuno-oncology, especially including new developments in immunotherapy 2.0. It is also designed to inform the decisions of leaders in companies and in academic groups that are working in areas that relate to cancer R&D and treatment.

For more information on the report, 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.

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Steven Rosenberg

On September 6, 2014, we published an article on this blog announcing the publication of our book-length report, Cancer Immunotherapy: Immune Checkpoint Inhibitors, Cancer Vaccines, and Adoptive T-cell Therapies, by Cambridge Healthtech Institute (CHI).

In that article, we cited the example of the case of a woman with metastatic cholangiocarcinoma (bile-duct cancer), which typically kills the patient in a matter of months. The patient, Melinda Bachini, was treated via adoptive immunotherapy with autologous tumor-infiltrating T cells (TILs) resulting in survival over a period of several years, with a good quality of life.

Our report includes a full discussion of that case, as of the date of the May 2014 publication of a report in Science by Steven A. Rosenberg, M.D., Ph.D. and his colleagues at the National Cancer Institute (NCI). Ms. Bachini’s story was also covered in a May 2014 New York Times article.

Now comes the publication, in Science on December 2015, of an update from the Rosenberg group on their clinical studies of TIL-based immunotherapy of metastatic gastrointestinal cancers. This article discusses the results of TIL treatment of ten patients with a variety of gastrointestinal cancers, including cancers of the bile duct, the colon or rectum, the esophagus, and the pancreas. The case of Ms. Bachini (“patient number 3737”) was included.

Ms. Bachini, a paramedic and a married mother of six children, and a volunteer with the Cholangiocarcinoma Foundation, was 41 years old when first diagnosed with cancer. She remains alive today—a five-year survivor—at age 46.

The Foundation produced a video, dated March 13, 2015, in which Ms. Bachini gives her “patient perspective”. This video includes her story “from the beginning”—from diagnosis through surgery and chemotherapy, and continuing with adoptive immunotherapy at the NCI under Dr. Rosenberg. Although her tumors continue to shrink and she remains alive, she still is considered to have “Stage 4” (metastatic) cancer. Ms. Bachini is a remarkable woman.

The Cholangiocarcinoma Foundation has also produced an on-demand webinar (dated October 21, 2014) on the adoptive cellular therapy trial in patients with various types of metastatic gastrointestinal cancers, led by Drs. Eric Tran and Steven Rosenberg. Ms. Bachini is also a presenter on that webinar. The December 2015 Science article is an updated version of the results of this trial.

The trial, a Phase 2 clinical study (NCT01174121) remains ongoing, and is recruiting new patients.

The particular focus of Dr. Tran’s and Dr. Rosenberg’s study in TIL treatment of gastrointestinal cancers is whether TILs derived from these tumors include T-cell subpopulations that target specific somatic mutations expressed by the cancers, and whether these subpopulations might be harnessed to successfully treat patients with these cancers. Of the ten patients who were the focus of the December 2015 publication, only Ms. Bachini had a successful treatment. In the case of Ms. Bachini, she received a second infusion of TILs that were enriched for CD4+ T cells that targeted a unique mutation in a protein known as ERBB2IP. It was this second treatment that resulted in the successful knockdown of her tumors, which continues to this day.

Despite the lack of similar successes in the treatment of the other nine patients, the researchers found that TILs from eight of these patients contained CD4+ and/or CD8+ T cells that recognized one to three somatic mutations in the patient’s own tumors. Notably, CD8+ TILs isolated from a colon cancer tumor of one patient (patient number 3995) recognized a mutation in KRAS known as KRAS G12D. This mutation results in an amino acid substitution at position 12 in KRAS, from glycine (G) to aspartic acid (D). KRAS G12D is a driver mutation that is involved in causation of many human cancers.

Although two other patients (numbers 4032 and 4069, with colon and pancreatic cancer, respectively) had tumors that expressed KRAS G12D, the researchers did not detect TILs that recognized the KRAS mutation in these patients. The researchers concluded that KRAS G12D was not immunogenic in these patients. The TILs from patient 3995 were CD8+ T cells that recognized KRAS G12D in the context of the human leukocyte antigen (HLA) allele HLA-C*08:02. [As with all T cells, TILs express T-cell receptors (TCRs) that recognize a specific antigenic peptide bound to a particular major histocompatibility complex (MHC) molecule—this is referred to as “MHC restriction”.] The two patients for whom KRAS G12D was not immunogenic did not express the HLA-C*08:02 allele.

The results seen with KRAS G12D-expressing tumor suggest the possibility of constructing genetically-engineered CD8+ T cells that express a TCR that is reactive with the KRAS mutation in the context of the HLA-C*08:02 allele. The KRAS G12D driver mutation is expressed in about 45% of pancreatic adenocarcinomas, 13% of colorectal cancers, and at lower frequencies in other cancers, and the HLA-C*08:02 allele is expressed by approximately 8% and 11% of white and black people, respectively, in the U.S. Thus, in the U.S. alone, thousands of patients per year with metastatic gastrointestinal cancers would potentially be eligible for immunotherapy with this KRASG12D-reactive T cell.

Although only Ms. Bachini (“patient number 3737”) was a long-term survivor, the researchers were able to treat three other patients with enriched populations of TILs targeting predominantly one mutated tumor antigen. Patient 4069 experienced a transient regression of multiple lung metastases of his pancreatic adenocarcinoma, but patients 4007 and 4032 had no objective response. Whereas 23% of circulating T cells at one month after treatment were adoptively transferred mutation-specific TILs in the case of Ms. Bachini, the other three patients treated with enriched populations of mutation-specific TILs showed no or minimal persistence. The researchers concluded that they will need to develop strategies designed to enhance the potency and persistence of adoptively transferred mutation-specific TILs. Nevertheless, the researchers concluded that nearly all patients with advanced gastrointestinal cancers harbor tumor mutation-specific TILs. This finding may serve as the basis for developing personalized adoptive cellular therapies and/or vaccines that can effectively target common epithelial cancers.

Conclusions

Dr. Rosenberg pioneered the study and development of adoptive cellular immunotherapy, beginning in the 1980s. Most studies with TIL-based adoptive immunotherapy have been in advanced melanoma. Adoptive cellular immunotherapy is the most effective approach to inducing complete durable regressions in patients with metastatic melanoma.

As we discussed in our cancer immunotherapy report, melanoma tumors have many more somatic mutations (about 200 nonsynonymous mutations per tumor) than most types of cancer. This appears to be due to the role of a potent immunogen—ultraviolet light—in the pathogenesis of melanoma. The large number of somatic mutations in melanomas results in the infiltration of these tumors by TILs that target the mutations. As discussed in our report, Dr. Rosenberg and his colleagues cultured TIL cell lines that addressed specific immunodominant mutations in patients’ melanomas. Treatment with these cell lines in several cases resulted in durable complete remissions of the patients’ cancers.

Dr. Rosenberg and his colleagues used the same strategy employed in identification of TIL cell lines that targeted specific mutations in melanomas to carry out the study in gastrointestinal cancers, as discussed in our report. However, the small number of somatic mutations and of endogenous TILs in gastrointestinal cancers and in most other epithelial cancers has made studies in these cancers more difficult than studies in melanoma.

in addition, the susceptibility of melanoma to treatment with checkpoint inhibitors such as the PD-1 blockers pembrolizumab (Merck’s Keytruda) and nivolumab (Bristol-Myers Squibb’s Opdivo) correlates with the large number of somatic mutations in this type of cancer. As we discussed in our December 15, 2014 article on this blog, immune checkpoint inhibitors work by reactivating endogenous tumor-infiltrating T cells (TILs). In the case of melanoma, these endogenous TILs target the numerous somatic mutations found in these cancers, and—as suggested by Dr. Rosenberg’s studies with cultured TIL cell lines—those endogenous TILs that target immunodominant mutations can induce durable compete remissions. As discussed in our December 15, 2014 blog article, the three major types of immuno-oncology treatments—immune checkpoint inhibitors, cancer vaccines, and adoptive T-cell therapies, work via related mechanisms.

In 2015, researchers showed that other types of cancers that have numerous somatic mutations are especially susceptible to checkpoint inhibitor treatment. These include, for example, non-small cell lung cancers (NSCLCs) that have mutational signatures that indicate that the cancers were caused by smoking, and cancers that have mutations in genes involved in DNA repair. (Mutations in genes involved in DNA repair pathways result in the generation of numerous additional mutations.)

Moreover, as discussed in our December 15, 2014 blog article, cancer immunotherapy researchers have been expanding the types of tumors that can be treated with checkpoint inhibitors. Genentech/Roche’s PD-L1 inhibitor that was discussed in that article, MPDL3280A, is now called atezolizumab. The clinical trials of atezolizumab discussed in that article and in our report have continued to progress. In a pivotal Phase 2 study in locally advanced or metastatic urothelial bladder cancer (UBC), atezolizumab shrank tumors in 27 percent of people whose disease had medium and high levels of PD-L1 expression and had worsened after initial treatment with platinum chemotherapy. These responses were found to be durable. According to Genentech, these results may represent the first major treatment advance in advanced UBC in nearly 30 years. Atezolizumab also gave positive results in Phase 2 clinical trials in patients with NSCLC that expresses medium to high levels of PD-L1.

Meanwhile, NewLink Genetics (Ames, IA) has entered Phase 3 clinical trials in pancreatic cancer with its HyperAcute cellular immunotherapy vaccine therapy. A Phase 2 trial of the company’s HyperAcute cellular immunotherapy algenpantucel-L in combination with chemotherapy and chemoradiotherapy in resected pancreatic cancer (clinical trial number NCT00569387) appears to be promising.

Dr. Rosenberg’s studies of TIL therapies of gastrointestinal cancers represent another approach to moving immuno-oncology treatments beyond melanoma, based on mutation-specific targeting. The types of cancers that form the focus of these studies—gastrointestinal epithelial cancers—have proven difficult to treat. Moreover, several of them are among the most common of cancers. The researchers and patients involved in these and other immuno-oncology studies are heroes, and oncologists appear to be making measured progress against cancers that have been until recently considered untreatable.

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.

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Cancer Cell

The 27 November issue of Nature contains a wealth of new studies on how immune checkpoint inhibitors target various types of cancer, and how researchers and physicians might be able to identify the patients who are most likely to benefit from treatment with these agents.

These studies are described in five papers published in that issue of Nature. This issue also contains a “News & Views” commentary on these articles by Drs. Jedd D. Wolchok and Timothy A. Chan (both at the Memorial Sloan Kettering Cancer Center). This article serves as an introduction to the five research articles.

In addition, Science Magazine published a commentary on these articles, entitled “Multiple boosts for cancer immunotherapy”, by contributing correspondent Mitch Leslie.

Checkpoint inhibitors can be used to treat several types of cancer

One important result of these studies is the expansion of the range of cancers that can be treated via immunotherapy beyond melanoma, kidney cancer, and non-small cell lung cancer (NSCLC). The papers by Powles et al. and Herbst et al. contain results from a Phase 1 clinical trial of Genentech’s monoclonal antibody (MAb) PD-L1 blocker MPDL3280A. Herbst et al. reported that MPDL3280A showed therapeutic responses in patients with NSCLC, melanoma, renal cancer, and head and neck cancer. Powles et al. focused on the effects of this agent in a larger group of patients with metastatic urothelial bladder cancer (UBC). In both reports, researchers documented that a subset of patients experienced durable responses, and that the treatment showed low toxicity.

We discussed earlier presentations of the results of the Phase 1 trial of MPDL3280A in our Insight Pharma Report (IPR), Cancer Immunotherapy: Immune Checkpoint Inhibitors, Cancer Vaccines, and Adoptive T-Cell Therapies. As we discussed in this report, the FDA granted breakthrough therapy designation for MPDL3280A for treatment of UBC. Roche/Genentech has initiated a Phase 2 clinical trial (clinical trial number NCT02108652) of MPDL3280A in UBC. UBC is the ninth most common cancer in the world. Metastatic UBC is associated with a poor prognosis, and has few treatment options. There have been no new treatment advances in nearly 30 years.

Checkpoint inhibitors work by reactivating tumor-infiltrating T cells (TILs)

Perhaps the most important finding of the research published in the November 27th issue of Nature is that checkpoint inhibitors work via reactivating endogenous tumor-infiltrating T cells. (These T cells are often called “TILs”, which is an acronym for “tumor-infiltrating lymphocytes”.)

For example, as described in the Powles et al. report, Genentech’s PD-L1 blocker MPDL3280A was found to be especially effective in treating patients whose tumors contained PD-L1-positive TILs. As we discussed in our IPR report, Genentech researchers found that MPDL3280A not only targets PD-L1 on the surface of tumor cells, but also PD-L1 on the surface of TILs. PD-L1 on activated T cells interacts not only with PD-1, but also with B7 on the surface of antigen presenting cells, sending a negative signal to the T cells. MPDL3280A targets the PD-L1-B7 interaction, thus enabling reactivation of PD-L1-bearing TILs so that they can attack the tumor.

As we also discuss in our report, targeting PD-1, PD-L1, and CTLA-4 may also be important in reversing immunosuppression by regulatory T cells (Tregs), which typically heavily infiltrate tumors. This provides another mechanism by which checkpoint inhibitors can reactivate TILs and thus induce anti-tumor immune responses.

As described in Powles et al, MPDL3280A was engineered with a modification in the Fc domain that eliminates antibody-dependent cellular cytotoxicity (ADCC). Genentech researchers did this because PD-L1 is expressed on activated T cells, and they wanted an anti-PD-L1 MAb agent that would reactivate these T cells, not destroy them via ADCC.

In the studies described by Herbst et al., researchers showed that Genentech’s PD-L1 blocker MPDL3280A gives antitumor response across multiple types of cancer, in tumors that expressed high levels of PD-L1. These responses especially occurred when PD-L1 was expressed by TILs. The studies suggest that MPDL3280A is most effective against tumors in which endogenous TILs are suppressed by PD-L1, and are reactivated via anti-PD-L1 MAb targeting.

In the Tumeh et al. study, the researchers found that patients responding to treatment with Merck’s MAb PD-1 blocker pembrolizumab (Keytruda) showed proliferation of intratumoral CD8+ T cells that correlated with reduction in tumor size. Pretreatment tumor samples taken from responding patients showed higher numbers of CD8, PD-1, and PD-L1 expressing cells at the invasive tumor margin and within tumors, with a close proximity between PD-1 and PD-L1, and a clonal TCR repertoire.

Based on this information, the researchers developed a predictive model based on CD8 expression at the invasive tumor margin. They validated this model in an independent 15-patient cohort. The researchers concluded that tumor regression due to treatment with the PD-1 blocker pembrolizumab requires preexisting CD8+ T cells whose activity has been blocked by PD-1/PD-L1 adaptive resistance. This study, like those of Powles et al. and Herbst et al., thus indicate that checkpoint inhibitors work against cancer by reactivating TILs. The Tumeh et al. study also indicates that CD8 expression at the invasive tumor margin is a predictive biomarker for sensitivity of patient tumors to treatment with anti-PD-1 checkpoint inhibitors.

The Powles, Herbst, and Tumeh reports all involved studies in human patients. However, the other two papers—Yadav et al. and Gubin et al. involve studies in mouse tumor models.

In the study of Yadav et al., the researchers used their mouse model to develop a method for discovering immunogenic mutant peptides in cancer cells that can serve as targets for T cells. They sequenced the exomes of two mouse cancer cell lines, and looked for differences with the corresponding normal mouse exomes. They also identified which of the neoantigens that they identified via exome sequencing could bind to histocompatibility complex class I (MHCI) proteins, and thus could be presented to T cells. They then modeled the MHC1/peptide complexes, and used these models to predict which of these neoantigens were likely to be immunogenic.

These methods identified only a few candidate neoantigens. Vaccination of tumor-bearing mice with these neoantigens resulted in therapeutically active T-cell responses. In addition, the researchers developed methods for monitoring the antitumor T cell response to peptide vaccination.

In the study of Gubin et al., the researchers used similar genomic and bioinformatic approaches to those of Yadav et al., and identified two neoantigens that were targeted by T cells following therapy with anti-PD-1 and/or anti-CTLA-4 antibodies. [Human CTLA-4 is the target of the checkpoint blockade inhibitor ipilimumab (Medarex/ Bristol-Myers Squibb’s Yervoy).] As with PD-1 and PD-L1 blockers, we discussed this agent in our IPR report. T cells specific for these neoantigens (in the context of MHCI proteins expressed by the mice) were present in the tumors. These T cells were reactivated by anti-PD-1 and/or anti-CTLA-4 antibodies, enabling the mice to reject the tumors.

As in the study of Yadav et al., the Gubin et al. researchers performed experiments in which they vaccinated tumor-bearing mice with peptides that incorporated the mutant epitopes. This vaccination induced specific tumor rejection that was comparable to treatment with checkpoint blockade inhibitors. As in the case of Yadav et al, the Gubin et al. researchers concluded that specific mutant antigens were targets of checkpoint inhibitor therapy in their mouse models, and that the mutant antigens could also be used to develop personalized cancer vaccines.

Since the studies of Yadav et al. and Gubin et al. were carried out using mouse tumor models, the results are not directly applicable to cancer in human patients. However, the studies suggest that immune checkpoint inhibitors work by reactivating endogenous TILs, and that anti tumor TILs work by attacking specific neoantigens on the tumors.

As we discussed in our IPR report, Dr. Steven Rosenberg (National Cancer Institute, Bethesda, MD) identified specific antigens that were the targets of TILs, both in metastatic melanoma and in metastatic cholangiocarcinoma (a type of epithelial bile duct cancer). However, these target antigens were from human cancers, and they were targets of TILs that has been isolated from patient tumors, cultured and expanded ex vivo, and used in adoptive cellular immunotherapy.

Moreover, the antigens were targets of TIL therapies that resulted in a durable compete remission in the case of the melanoma patient, and long-term tumor regression in the case of the metastatic cholangiocarcinoma patient. The metastatic cholangiocarcinoma case was highlighted in our September 16, 2014 Biopharmconsortium Blog article.

The Yadav et al. paper referenced the Rosenberg group’s work. However, this paper stated that “few mutant epitopes have been described because their discovery required the laborious screening of patient tumour-infiltrating lymphocytes for their ability to recognize antigen libraries constructed following tumour exome sequencing.”

The methods of Yadav et al. (and of Gubin et al.) are thus designed to simplify and accelerate the discovery of immunogenic mutant peptides. They carried out their studies in mouse models, which helped these researchers to develop methods that could potentially discover greater numbers of neoantigens more efficiently. However, it remains to be seen to what extent they can apply their methods to human patients.

Unifying the field of immuno-oncology

As can be seen, for example, from the title of our IPR report, the three major approaches to immuno-oncology in 2014/2015 are development of immune checkpoint inhibitors, of cancer vaccines, and of adoptive T-cell therapies.

In the immuno-oncology papers published in the 27 November issue of Nature, researchers show that checkpoint inhibitors work via reactivating of endogenous TILs. They also (in mouse tumor models) identified neoantigens that are targets of these reactivated TILs, and designed peptide vaccines that were as effective as checkpoint inhibitor therapy in the mouse models. In principle, one can isolate TILs that are reactive to particular neoantigens in the mouse tumors, culture and expand them ex vivo, and infuse them back into the mice to target their tumors. Thus the studies in the 27 November issue of Nature serve as a template for the unification of the immuno-oncology field as it now exists.

However, it will be necessary to apply the methodologies developed by Yadav et al. and Gubin et al. to human patients. And at least so far, peptide vaccines have not been very successful in treating patients, as compared to TIL therapy (in the subset of patients in whom TIL therapy can be done). It is thus possible that once these methods of neoantigen identification are applied to human patients, it will be found that targeting the neoantigens with ex vivo-expanded TILs will be more successful than therapy with peptide vaccines. However, whether this is true awaits the application of the new methodologies to neoantigen identification in human tumors.

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.

The post Immune checkpoint inhibitors work by reactivating tumor-infiltrating T cells (TILs) appeared first on Haberman Associates.

Maraviroc

In April 2012, Informa’s Scrip Insights published our book-length report, “Advances in the Discovery of Protein-Protein Interaction Modulators.” We also published a brief introduction to this report, highlighting the strategic importance of protein-protein interaction (PPI) modulators for the pharmaceutical industry, on the Biopharmconsortium Blog.

The report included a discussion on discovery and development of inhibitors of chemokine receptors. Chemokine receptors are members of the G-protein coupled receptor (GPCR) superfamily. GPCRs are seven-transmembrane (7TM) domain receptors (i.e. integral membrane proteins that have seven membrane-spanning domains). Compounds that target GPCRs represent the largest class of drugs produced by the pharmaceutical industry. However, in the vast majority of cases, these compounds target GPCRs that bind to natural small-molecule ligands.

Chemokine receptors, however, bind to small proteins, the chemokines. These proteins constitute a class of small cytokines that guide the migration of immune cells via chemotaxis. Chemokine receptors are thus a class of GPCRs that function by forming PPIs. Direct targeting of interactions between chemokines and their receptors (unlike targeting the interactions between small-molecule GPCR ligands and their receptors) thus involves all the difficulties of targeting other types of PPIs.

However, GPCRs–including chemokine receptors–appear to be especially susceptible to targeting via allosteric modulators. Allosteric sites lie outside the binding site for the protein’s natural ligand. However, modulators that bind to allosteric sites change the conformation of the protein in such a way that it affects the activity of the ligand binding site. (Direct GPCR modulators that bind to the same site as the GPCR’s natural ligands are known as orthosteric modulators.) In the case of chemokine receptors, researchers can in some cases discover small-molecule allosteric modulators that activate or inhibit binding of the receptor to its natural ligands. Discovery of such allosteric activators is much easier than discovery of direct PPI modulators.

Chemokines bind to sites that are located in the extracellular domains of their receptors. Allosteric sites on chemokine receptors, however, are typically located in transmembrane domains that are distinct from the chemokine binding sites. Small-molecule allosteric modulators that bind to these sites were discovered via fairly standard medicinal chemistry and high-throughput screening, sometimes augmented with structure-based drug design. This is in contrast to attempts to discover small molecule agents that directly inhibit binding of a chemokine to its receptor, which has so far been extremely challenging.

Our report describes several allosteric chemokine receptor modulators that are in clinical development, as well as the two agents that have reached the market. One of the marketed agents, plerixafor (AMD3100) (Genzyme’s Mozobil), is an inhibitor of the chemokine receptor CXCR4. It is used in combination with granulocyte colony-stimulating factor (G-CSF) to mobilize hematopoietic stem cells to the peripheral blood for autologous transplantation in patients with non-Hodgkin lymphoma and multiple myeloma. The other agent, which is the focus of this blog post, is maraviroc (Pfizer’s Selzentry/Celsentri).

Maraviroc is a human immunodeficiency virus-1 (HIV-1) entry inhibitor. This compound is an antagonist of the CCR5 chemokine receptor. CCR5 is specific for the chemokines RANTES (Regulated on Activation, Normal T Expressed and Secreted) and macrophage inflammatory protein (MIP) 1α and 1β.  In addition to being bound and activated by these chemokines, CCR5 is a coreceptor (together with CD4) for entry of the most common strain of HIV-1 into T cells. Thus maraviroc acts as an HIV entry inhibitor; this is the drug’s approved indication in the U.S. and in Europe. Maraviroc was discovered via a combination of high-throughput screening and optimization via standard medicinal chemistry.

New structural biology studies of the CCR5-maraviroc complex

Now comes a report in the 20 September 2013 issue of Science on the structure of the CCR5-maraviroc complex. This report was authored by a mainly Chinese group led by Beili Wu, Ph.D. (Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai); researchers at the University of California at San Diego and the Scripps Research Institute, San Diego were also included in this collaboration. A companion Perspective in the same issue of Science was authored by P. J. Klasse, M.D., Ph.D. (Weill Cornell Medical College, Cornell University, New York, NY).

As described in the Perspective, the outer surface of the HIV-1 virus displays numerous envelope protein (Env) trimers, each including the outer gp120 subunit anchored in the viral membrane by gp41. When gp120 binds to the cell-surface receptor CD4, this enables interaction with a specific chemokine receptor, either CCR5 or CXCR4. Interaction with both CD4 and the chemokine receptor triggers complex sets of changes in the Env complex, eventually resulting in the fusion of the viral membrane and the cell membrane, and the entry of the virus particle into the host cell.

HIV-1 gp120 makes contact with CCR5 at several points. The interactions between CCR5 and the variable region of gp120 called V3 are especially important for the tropism of an HIV-1 strain, i.e., whether the virus is specific for CCR5 (the “R5 phenotype”) or CXCR4 (the “X4 phenotype”). In the case of R5-tropic viruses, the tip of the V3 region interacts with the second extracellular loop (ECL2) of CCR5, while the base of V3 interacts with the amino-terminal segment of CCR5. Modeling of the interactions between the V3 domain of gp120 of either R5 or X4-tropic viruses with CCR5 or CXCR4 explains coreceptor use, in terms of forming strong bonds or–conversely–weak bonds and steric hindrance.

Monogram Biosciences (South San Francisco, CA) has developed and markets the Trofile assay. This is a molecular assay designed to identify the R5, X4, or mixed tropism of a patient’s HIV strain. If a patient’s strain is R5-tropic, then treatment with maraviroc is appropriate. However, a patient’s HIV-1 strain may undergo a tropism switch, or may mutate in other ways to become resistant to maraviroc.

Dr Wu and her colleagues determined the high-resolution crystal structure of the complex between maraviroc and a solubilized engineered form of CCR5. This included determining the CCR5 binding pocket for maraviroc, which was determined both by Wu et al’s X-ray crystallography, and by site-directed mutagenesis (i.e., to determine amino acid residues that are critical for maraviroc binding) that had been published earlier by other researchers.

The structural studies of Dr. Wu and her colleagues show that the maraviroc-binding site is different from the recognition sites for gp120 and for chemokines, as expected for an allosteric inhibitor. The X-ray structure shows that maraviroc binding prevents the helix movements that are necessary for binding of g120 to induce the complex sequence of changes that result in fusion between the viral and cellular membranes. (These helix movements are also necessary for induction of signal transduction by binding of chemokines to CCR5.)

Structural studies of CXCR4 and its inhibitor binding sites

In addition to their structural studies of the CCR5-maraviroc complex, Dr. Wu and her colleagues also published structural studies of CXCR4 complexed with small-molecule and cyclic peptide inhibitors in Science in 2010. These inhibitors are IT1t, a drug-like orally-available isothiourea developed by Novartis, and CVX15, a 16-residue cyclic peptide that had been previously characterized as an HIV-inhibiting agent. IT1t and CVX15 bind to overlapping sites in CXCR4. Other researchers have found evidence that the binding site for plerixafor also overlaps with the IT1t binding site.

As discussed in Wu et al’s 2013 paper, CCR5 and CXCR4 have similar, but non-identical structures. The binding site for IT1t in CXCR4 is closer to the extracellular surface than is the maraviroc binding site in CCR5, which is deep within the CCR5 molecule. The entrance to the CXCR4 ligand-binding pocket is partially covered by CXC4’s N terminus and ECL2, but the CCR5 ligand-binding pocket is more open.

Mechanisms of CXCR4 and CCR5 inhibition, and implications for discovery of improved HIV entry inhibitors

The chemokine that specifically interacts with the CXCR4 receptor is known as CXCL12 or stromal cell-derived factor 1 (SDF-1). Researchers have proposed a hypothesis for how CXCL12 interacts with CXCR4; this hypothesis appears to be applicable to the interaction between other chemokines and their receptors as well. This hypothesis is know as the “two-step model” or the “two-site model” of chemokine-receptor activation. Under the two-site model, the core domain of a chemokine binds to a site on its receptor (known as the “chemokine recognition site 1” or “site 1”) defined by the receptor’s N-terminus and its ECLs. In the second step, the flexible N-terminus of the chemokine interacts with a second site (known as “chemokine recognition site 2” or “site 2” or the “activation domain”) deeper within the receptor, in transmembrane domains. This result in activation of the chemokine receptor and intracellular signaling.

Under the two-site model, CXCR4 inhibitors (e.g., IT1t, CVX15, and  plerixafor), which bind to sites within the ECLs of CXCR4, are competitive inhibitors of binding of the core domain of CXCL12 to CXCR4 (i.e.., step 1 of chemokine/receptor interaction). They are thus orthosteric inhibitors of CXCR4. (This is contrary to the earlier assignment of plerixafor as an allosteric inhibitor of CXCR4.)  The CCR5 ligand maraviroc, however, binds within a site within the transmembrane domains of CCR5, which overlaps with the activation domain of CCR5. Dr. Wu and her colleagues propose two alternative hypotheses: 1. Maraviroc may inhibit CCR5 activation by chemokines by blocking the second step of chemokine/chemokine receptor interaction, i.e., receptor activation. 2. Maraviroc may stabilize CCR5 in an inactive conformation. It is also possible that maraviroc inhibition of CCR5 may work via both mechanisms.

Dr. Wu and her colleagues further hypothesize that the interaction of  HIV-1 gp120 with CCR5 (or CXCR4) may operate via similar mechanisms to the interaction of chemokines with their receptors. As we discussed earlier in this article, the base (or the stem region) of the gp120 V3 domain interacts with the amino-terminal segment of CCR5. The tip (or crown) of the V3 domain interacts with the ECL2 of CCR5, and–according to Dr. Wu and her colleagues–also with amino acid residues inside the ligand binding pocket; i.e., the activation site of CCR5. The HIV gp120 V3 domain may thus activate CCR5 via a similar mechanism to the two-step  model utilized by chemokines.

Based on their structural biology studies, Dr. Wu and her colleagues have been building models of the CCR5-R5-V3 and CXC4-X4-V3 complexes, and are also planning to determine additional structures needed to fully understand the mechanisms of HIV-1 tropism. The researchers will utilize their studies in the discovery of improved, second-generation HIV entry inhibitors for both R5-tropic and X4-tropic strains of HIV-1.

The bigger picture

The 17 October 2013 issue of Nature contains a Supplement entitled “Chemistry Masterclass”. In that Supplement is an Outlook review entitled “Structure-led design”, by Nature Publishing Group Senior Editor Monica Hoyos Flight, Ph.D. The subject of this article is structure-based drug design of modulators of GPCRs.
This review outlines progress in determining GPCR structures, and in using this information for discovery of orthosteric and allosteric modulators of GPCRs.

According to the article, the number of solved GPCR structures has been increasing since 2008, largely due to the efforts of the Scripps GPCR Network, which was established in that year. Dr. Wu started her research on CXCR4 and CCR5 as a postdoctoral researcher in the laboratory of Raymond C. Stevens, Ph.D. at Scripps in 2007, and continues to be a member of the network. The network is a collaboration that involves over a dozen academic and industrial labs. Its goal has been to characterize at least 15 GPCRs by 2015; it has already solved 13.

Interestingly, among the solved GPCR structures are those for the corticotropin-releasing hormone receptor and the glucagon receptor. Both have peptide ligands, and thus work by forming PPIs.

One company mentioned in the article, Heptares Therapeutics (Welwyn Garden City, UK), specializes in discovering new medicines that targeting previously undruggable or challenging GPCRs. In addition to discovering small-molecule drugs, Heptares, working with monoclonal antibody (MAb) leaders such as MorphoSys and MedImmune, is working to discover MAbs that act as modulators of GPCRs. Among Heptares’ targets are several GPCRs with peptide ligands.

Meanwhile, Kyowa Hakko Kirin Co., Ltd. has developed the MAb drug mogamulizumab (trade name Poteligeo), which is approved in Japan for treatment of relapsed or refractory adult T-cell leukemia/lymphoma. Mogamulizumab targets CC chemokine receptor 4 (CCR4).

Thus, aided in part by structural biology, the discovery of novel drugs that target GPCRs–including those with protein or peptide targets such as chemokine receptors–continues to make progress.

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.

The post Chemokine receptors and the HIV-1 entry inhibitor maraviroc appeared first on Haberman Associates.

PD-L1

On June 28, 2012 we published an article on this blog entitled “Cancer Immunotherapy: The Star Of The 2012 ASCO Annual Meeting”. Now comes the American Society of Clinical Oncology (ASCO) 2013 Annual Meeting, which took place from May 30 to June 3, 2013.

As in 2012, cancer immunotherapy was the star of the meeting.

In our June 2012 article, we focused on experimental monoclonal antibody (MAb) drugs that target the cell surface receptors programmed cell death-1 (PD-1) and programmed cell death-1 ligand (PD-L1). PD-1 is a member of the CD28/CTLA4 family of T cell regulators. Like CTLA4, the target of ipilimumab, PD-1 is a negative regulator of T-cell receptor signals. When PD-L1, which is a protein on the surface of some tumor cells, binds to PD-1 on T cells that recognize antigens on these tumor cells, this results in the blockage of the ability of the T cells to carry out an anti-tumor immune response. Anti-PD-1 MAb binds to PD-1 on T cells, thus preventing PD-L1 on tumor cells from binding to the PD-1 and initiating an inhibitory signal. Anti-tumor T cells are then free to initiate immune responses against the tumor cells. This mechanism of action is completely analogous to that of ipilimumab, which binds to CTLA4 and thus prevents negative signaling from that molecule.

Anti-PD-L1 therapeutics bind to PD-L1 on tumor cells. Ira Mellman (vice-president of research oncology at Genentech), believes that anti-PD-L1 might have fewer adverse effects than anti-PD-1. That is because anti-PD-L1 would target tumor cells while leaving T cells free to participate in immune networks that work to prevent autoimmune reactions.

Three experimental drugs in this area of immunotherapy were a main focus at ASCO in 2013. They are:

• BMS’ anti-PD-1 agent nivolumab (BMS-936558, MDX-1106), which we had discussed in our 2012 ASCO article.
• Merck’s anti-PD-1 agent lambrolizumab (MK-3475)
• Roche/Genentech’s anti-PD-L1 agent MPDL3280A

We shall focus on these three agents in this article.

Competition between BMS’ nivolumab and Merck’s lambrolizumab

As highlighted in the 2013 ASCO meeting and in reports by industry commentators such as FierceBiotech, there is a keen race between BMS and Merck to be the first to market an anti-PD-1 agent.

At the ASCO 2013 meeting, BMS researchers and their colleagues reported that a third of the patients in a Phase 1 trial of nivolumab saw tumors shrink at least 30%. They also reported that patients with solid tumors [metastatic melanoma, non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC)] showed high rates of 2 year overall survival–44% for melanoma, 32% for NSCLC, and 52% for RCC (clinical trial NCT00730639).

In a first Phase 1 study of a combination therapy of nivolumab with ipilimumab in metastatic melanoma, BMS researchers and their colleagues reported that the two agents could be administered in combination safely. Clinical activity for the combination therapy appeared to exceed that of published monotherapy data for each of the two agents, with greater or equal to 80% tumor reduction at 12 weeks in 30% (11/37) of patients. In addition to the ASCO 2013 presentation, the results of this combination therapy trial were published online in the New England Journal of Medicine.

According to Fierce Biotech, BMS has 6 late-stage studies under way for nivolumab, with fast-track status in place for melanoma, lung cancer and kidney cancer.

Meanwhile, Merck announced in a June 2, 2013 press release the presentation at ASCO 2013 of interim data from a Phase 1B study evaluating its anti-PD-1 agent lambrolizumab in patients with advanced melanoma. The data was presented by Antoni Ribas, M.D., Ph.D. (Jonsson Comprehensive Cancer Center, University of California, Los Angeles). in addition to the ASCO 2013 presentation, this study was published online in the New England Journal of Medicine.

A total of 135 patients with advanced melanoma were treated. Most of the adverse events seen in the study were low grade. The confirmed response rate across all dose cohorts was 38%. The highest confirmed response rate (52%) was seen in the cohort that received the highest dose (10 mg per kilogram every 2 weeks). Ten percent of the patients in the highest-dose group achieved a complete response, with response duration ranging from 28 days to 8 months.

Response rates did not differ significantly between patients who had received prior ipilimumab treatment and those who had not. Responses were durable in the majority of patients; 81% of the patients who had a response (42 out of of 52 total) were still receiving treatment at the time of analysis in March 2013. The overall median progression-free survival among the 135 patients was over 7 months.

According to Fierce Biotech, Merck now has four clinical studies under way for lambrolizumab, including a  Phase 2 trial in melanoma and Phase 1 trials in ipilimumab-naïve patients with triple-negative breast cancer, metastatic bladder cancer and head and neck cancer. The company, which has won breakthrough drug designation from the FDA for lambrolizumab, believes that the ongoing 500-patient Phase 2 melanoma study could provide enough positive data to win FDA approval. Merck is also preparing applications for late-stage clinical trials in melanoma and non-small cell lung cancer, which are planned to launch in the third quarter of 2013.

Roche/Genentech’s anti-PD-L1 agent MPDL3280A

Genentech researchers and their collaborators presented data on a clinical study of MPDL3280A in patients with metastatic melanoma at ASCO 2013. In addition to the ASCO 2013 presentation and abstract, The Angeles Clinic and Research Institute (Los Angeles, CA) published a press release about the study. Omid Hamid, M.D. of The Angeles Clinic and Research Institute made the oral presentation at the ASCO meeting.

This study was a Phase 1, multicenter, first in human, open-label, dose escalation study (clinical trial NCT01375842), which is still ongoing. It was primarily designed to assess  safety, tolerability, and pharmacokinetics of MPDL3280A in patients with metastatic melanoma. The drug was found to be well tolerated. 35 patients who began treatment at doses of 1-20 mg/kg and were enrolled prior to Jul 1, 2012 were evaluable for efficacy. An overall response rate of 26% (9/35) was observed, with all responses ongoing or improving. Some responding patients experienced tumor shrinkage within days of initial treatment. The 24-week progression-free survival was 35%. Several other patients had delayed antitumor activity after apparent tumor progression. Of three initial patients treated with a combination of MPDL3280A and vemurafenib (Daiichi Sankyo/Genentech’s Zeboraf, a targeted kinase inhibitor), two experienced tumor shrinkage, including 1 complete response. The researchers concluded that further assessment of MPDL3280A as monotherapy and combination therapy is warranted. A Phase 1 study (NCT01656642) of a combination therapy of MPDL3280A and vemurafenib in patients with previously untreated BRAFV600-mutation positive metastatic melanoma is ongoing.

Data was also presented at ASCO 2013 on the efficacy of MPDL3280A in other solid tumors. According to Roy S. Herbst, M.D. Ph.D., (Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven) MPDL3280A showed significant anti-tumor activity and was well tolerated in patients with such cancers as NSCLC, melanoma, colorectal cancer, gastric cancer, and RCC. 29 of 140 evaluable patients (21%) exhibited tumor shrinkage, with the highest overall responses in patients with NSCLC and melanoma. Of the 29 responders, 26 patients continued responding as of their last assessment.

Researchers have also been studying PD-L1 expression levels as a potential biomarker to identify likely responders. As outlined by Dr. Herbst, responses appeared to be better among patients with higher levels of PD-L1 expression. The response rate among PD-L1-positive patients was 36% (13 of 36 patients), compared with 13% (9 of 67 patients) who were PD-L1-negative. The role that PD-L1 expression might play as a biomarker is still being explored, including attempting to determine the best way to measure the protein and other related criteria.

In addition to the Phase 1 trial of MPDL3280A/vemurafenib combination therapy in melanoma, Genentech is sponsoring a Phase 1 trial of MPDL3280A in combination with bevacizumab (Genentech/Roche’s Avastin, an angiogenesis inhibitor that targets vascular endothelial growth factor) or with bevacizumab plus chemotherapy (clinical trial NCT01633970). Genentech is also sponsoring a Phase 2 clinical trial (NCT01846416) of MPDL3280A in patients With PD-L1-positive advanced NSCLC.

Conclusions

The field of immunotherapeutic MAbs for cancer, which target negative regulators of T-cell receptor signals, continues to advance. The approval and marketing of ipilimumab provides an important proof-of-principle for this approach. Now the field is advancing to include agents that target PD-1 and its negative regulator PD-L1. Studies of BMS’ PD-1 inhibitor nivolumab have advanced as far as Phase 3, and of Merck’s lambrolizumab as far as Phase 2. Meanwhile, Roche/Genentech’s PD-L1 inhibitor MPDL3280A has reached Phase 2.

However, the in terms of clinical trial data, it is still too early to meaningfully determine the efficacy of any of the PD-1 and PD-L1 inhibitor drugs. The meaningful data will come from randomized Phase 3 trials, based on overall survival rather than tumor response rate as in currently reported trials (with the exception of the Phase 1 results of clinical trial NCT00730639 of nivolumab described earlier, which included measures of overall survival).

Nevertheless, this is an extremely exciting field, and researchers, companies, and patient communities have high expectations of success.

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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.

The post Cancer immunotherapy: the star of the ASCO Annual Meeting two years in a row! appeared first on Haberman Associates.

Pittsburgh compound B staining in AD. Source: National Institute on Aging/NIH.

In our February 28, 2013 article on the Biopharmconsortium Blog, we discussed the FDA’s February 7, 2013 Draft Guidance for Industry entitled “Alzheimer’s Disease: Developing Drugs for the Treatment of Early Stage Disease”.

This document had been distributed for comment purposes only, and the FDA has been seeking public comment on the draft guidance for 60 days following publication.

As we discussed, by issuing this Draft Guidance, the FDA added its voice to that of an ever-increasing segment of the scientific community that calls for a new focus on conducting clinical trials in early-stage Alzheimer’s disease (AD). This is in order to  focus industry R&D on developing treatments for patients whose disease is in a stage prior to the development of extensive irreversible brain damage. It is in this early stage of disease in which researchers believe that new drugs have the best chance of providing benefits to patients, by preventing further damage to the brain.

In our February 28, 2013 article, we also discussed several clinical trials being carried out by industry and academic researchers in early-stage AD. These trials should allow the scientific and medical community to answer the question as to whether treating patients with pre-AD or very early-stage AD with anti-amyloid MAb drugs can have a positive effect on the course of the disease, and slow or prevent cognitive decline.

Readers of our article may have noticed that the February 7, 2013 Draft Guidance was somewhat vague or confused. That is because there is currently no evidence-based consensus as to which biomarkers might be appropriate to support clinical findings in trials in early AD. Moreover, in “pre-AD” or very early-stage AD (i.e., before the onset of overt dementia) disease-related impairments are extremely challenging to assess accurately. Thus both measuring clinical outcomes and assessment via biomarkers in very early-stage AD are fraught with difficulty, making determination of drug efficacy very difficult.

In issuing the Draft Guidance, The FDA appeared to be seeking guidance from industry and from the academic community on how these issues might be resolved. As we said in our article, the early-stage AD trials now in progress might help the scientific and medical community, and the FDA, with issues of evaluation of biomarkers and clinical outcome measures in determining disease prognosis and the efficacy of drug treatments.

More recently–on March 13, 2013–the FDA proposed a further modification of its proposed guidelines for regulation of early-stage AD therapeutics. This was published online in an article in the New England Journal of Medicine (NEJM), entitled “Regulatory Innovation and Drug Development for Early-Stage Alzheimer’s Disease”, by Nicholas Kozauer, M.D. and Russell Katz, M.D. (As we stated in our earlier article, Dr.Katz is the director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. Dr. Kozauer is a Clinical Team Lead in the same division of the FDA.)

The new proposal attempts to deal with some of the apparent confusion in the February 7, 2013 Draft Guidance, and to facilitate the development and approval of new drugs for early-stage AD. The NEJM article notes that traditional measures of AD drug efficacy at the FDA had included assessment both of improved cognition and improvements in function. Specifically, as stated by a New York Times article discussing the new FDA proposal, “cognition” refers to such mental processes as memory and reasoning (as assessed by various tests), and “function” refers to performing such day-to-day activities as cooking, dressing or bathing.

In the FDA’s March 13, 2013 NEJM article, the authors note that researchers and regulatory agencies “simply do not yet have drug-development tools that are validated to provide measures of function in patients with Alzheimer’s disease before the onset of overt dementia”. Thus, although one can test early-stage AD patients for improvements in cognition with the appropriate tests, testing for deficits and improvements in function is extremely difficult.

The authors of the NEJM article therefore suggest that it might be feasible that a drug for treating early-stage AD be approved via the FDA’s accelerated approval pathway, on the basis of assessment of cognitive outcome alone. The agency’s accelerated-approval pathway allows drugs that address an unmet medical need to be approved on the basis of a surrogate or an intermediate clinical endpoint–in this case, a sensitive measure of improvement in cognition. Drugs approved via “accelerated approval” must be subjected to postmarketing studies to verify the clinical benefit. This regulatory pathway might facilitate the approval of treatments that appear to be effective in early AD, when patients might be expected to derive a greatest benefit than after the development of overt dementia.

With respect to selection of patients for trials in early-stage AD, the authors of the NEJM article suggest that (based on “the consensus emerging within the AD research community”) clinical diagnosis of early cognitive impairment be combined with appropriate biomarkers. These biomarkers might include brain amyloid load [as measured by positron-emission tomography (PET)] and cerebrospinal fluid levels of β-amyloid and tau proteins. The FDA places a high priority on efforts by the researchers to qualify such biomarkers in clinical trial design in early-stage AD.

The author of the New York Times article, veteran science and medicine reporter Gina Kolata, says that the FDA’s new proposal could “help millions of people at risk of developing [AD] by speeding the development and approval of drugs that might slow or prevent it.”

She also says that the proposal could be a boon for the pharmaceutical industry and AD researchers. They have often been hampered by regulations that left them uncertain of how to get drugs tested and approved for early-stage AD. Not only might anti-AD therapies provide greater benefit to patients with early-stage AD than with later stage disease, but clinical trials in early-stage AD would have a greater potential for success–provided that researchers had appropriate means of determining efficacy in early-stage AD. The new FDA proposal may increase the likelihood of identifying such appropriate means.

As pointed out in the Times article, several leading AD researchers agree, with some important caveats. For example, AD researcher P. Murali Doraiswamy, M.D. (Duke University School of Medicine) said that the new proposed regulations would lead to more clinical trials, and more motivation now to invest in the AD field. However, many companies never manage to do postmarking studies required for drugs given accelerated approval, and such studies might not be randomized clinical trials as required in gaining approval of the drugs in the first place.

Sean Bohen, M.D., Ph.D. (Senior Vice President for Early Development at Genentech) was very positive about the proposed new FDA policy, but wondered how researchers could develop appropriate tests to identify subtle cognitive changes in early AD or pre-AD. Nevertheless, he said, “We have to start somewhere.”

Thus clinical trials in early-stage AD, and development of regulatory frameworks for approval and postmarketing studies of agents that emerge from these trials, remain a work in progress.

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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 an initial one-to-one consultation on an issue that is key to your company’s success, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

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Normal and Alzheimer’s brains compared.

Once again, approaches to improving clinical trials for candidate disease-modifying drugs for Alzheimer’s disease (AD) are in the news. On February 7, 2013, the FDA issued a Draft Guidance for Industry entitled “Alzheimer’s Disease: Developing Drugs for the Treatment of Early Stage Disease”.

This document has been distributed for comment purposes only, and the FDA is seeking public comment on the draft guidance for 60 days.

The wording of the Draft Guidance illustrates the extreme difficulty of defining populations with pre-AD or very early-stage AD, and of demonstrating the efficacy of a drug in ameliorating early-stage disease, and/or in preventing its progression to later-stage disease. The document states that the FDA is “open to considering the argument that a positive biomarker result (generally included as a secondary outcome measure in a trial) in combination with a positive finding on a primary clinical outcome measure may support a claim of disease modification in AD.”

However,  there is currently no evidence-based consensus as to which biomarkers might be appropriate to support clinical findings in trials in early AD. Moreover, in “pre-AD” or very early-stage AD (i.e., before the onset of overt dementia) mild disease-related impairments are extremely challenging to assess accurately. Thus both measuring clinical outcomes and assessment via biomarkers in very early-stage AD are fraught with difficulty, making determination of drug efficacy extremely difficult. The FDA thus appears to be seeking guidance from industry and from the academic community on how these knotty problems might be solved.

The move toward conducting clinical trials in early-stage AD patients

By issuing the Draft Guidance, the FDA adds its voice to that of an ever-increasing segment of the scientific community that calls for a new focus on conducting clinical trials in early-stage AD. We discussed this trend in our August 19, 2012 and August 28, 2012 articles on the Biopharmconsortium Blog.

As we discussed, this trend is driven in part by the Phase 3 failures of Pfizer/Janssen’s bapineuzumab and Lilly’s solanezumab in 2012. Now–in February 2013–Russell Katz, M.D. (director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research) says, “The scientific community and the FDA believe that it is critical to identify and study patients with very early Alzheimer’s disease before there is too much irreversible injury to the brain. It is in this population that most researchers believe that new drugs have the best chance of providing meaningful benefit to patients.”  In line with this statement, the FDA refused to entertain Lilly’s  secondary analysis of early stage patients in the solanezumab study that we discussed in our August 28, 2012 blog article. Instead, the FDA mandated that Lilly conduct a new Phase 3 trial that will exclude the moderate-stage patients who hadn’t responded, and focus only on early-stage patients.

Recent news on clinical trials in early-stage AD

Despite the difficulties highlighted in the Draft Guidance in conducting clinical trials in early-stage AD patients, three research groups are actually conducting such trials. We outlined these studies in our August 28, 2012 blog article, and discussed one of these studies, the one begin carried out by Genentech, in greater detail in our August 19 2012 article.

The three studies are:

• Roche/Genentech’s Phase 2a trial of its its anti-amyloid MAb crenezumab, in presymptomatic members of a large Colombian kindred who harbor a mutation in presenilin 1 (PS1) that causes dominant early−onset familial AD.

• Studies conducted in conjunction with the Dominantly Inherited Alzheimer Network (DIAN), a consortium led by researchers at Washington University School of Medicine (St. Louis, MO). This study will include people with mutations in any of the three genes linked to early-stage, dominantly-inherited AD–PS1, PS2, and amyloid precursor protein (APP). Initial studies focused on changes in biomarkers and in cognitive ability as a function of expected age of AD onset in people with these mutations. These included changes in concentrations of amyloid-β1–42 (Aβ42) in cerebrospinal fluid (CSF), and amyloid accumulation in the brain. In the first stage of the actual trial, three drugs (which have not yet been selected) will be tested in this population, and changes in biomarkers and cognitive performance will be followed.

• The Anti-Amyloid Treatment of Asymptomatic Alzheimer’s (A4) trial, will involve treating adults without mutations in any of the above three genes, whose brain scans show signs of amyloid accumulation. A4 is thus designed to study prevention of sporadic AD (by far the most common form of the disease). It will enroll 500 people age 70 or older who test positive on a scan of amyloid accumulation in the brain. (This is in contrast to the two trials in subjects with gene mutations, who are typically in their 30s or 40s.) A4 will also have a control arm of 500 amyloid-negative subjects. Amyloid-positive and control subjects will be entered into a three-year double-blind clinical trial that will look at changes in cognition with drug treatment. The A4 researchers [led by Reisa Sperling, Brigham and Women’s Hospital/Harvard University (Boston, MA), and Paul Aisen, University of California, San Diego] planned to select a drug for testing by December 2012.

Now there is more recent news on two of these trials.

1. On December 13, 2012, the Los Angeles Times reported that Genentech and its collaborators [affiliated with the University of Antioquia medical school (Medellin, Colombia), the University of California at Los Angeles (UCLA), and the Banner Alzheimer’s Institute (Phoenix, AZ)] will begin their $100 million clinical trial of crenezumab with 100 Colombians who carry the PS1 mutation in the spring of 2013. Genentech is contributing $65 million of the study’s $100-million cost. The NIH and the Banner Alzheimer’s Institute (Phoenix, AZ) are financing the remainder.

This story was also reported on December 14, 2012 by Fierce Biotech.

The design of the trial calls for 100 additional patients in Colombia with the same Alzheimer’s-related gene to receive a placebo, and an equal number of other at-risk patients without the gene to take crenezumab.  A branch of the trial will include U.S. patients as well. A “branch study” will also be conducted at UCLA, where researchers have discovered a similar genetic disposition among members of an extended family from Jalisco, Mexico. Some 30 individuals from this family who have immigrated to Southern California could participate. Around 150 other U.S. patients with similar mutations will also participate in the trial.

The trial is designed to provide evidence that targeting amyloid with crenezumab at an early stage or even before patients show signs of dementia can have a positive effect on the course of disease.

2. On January 18, 2013, Fierce Biotech reported that the researchers conducting the A4 study have chosen Lilly’s solanezumab as as the first therapeutic drug candidate to be evaluated in the trial. The A4 trial’s principal investigator, Reisa Sperling said that the researchers chose solanezumab (after considering a number of anti-amyloid drugs) because the compound has a good safety profile, and appeared to show a modest clinical benefit in the mild AD patients in Lilly’s Phase 3 trial. The A4 researchers’ confidence in solanezumab grew when this was confirmed via an independent academic analysis by the Alzheimer’s Disease Cooperative Study (ADCS), a consortium of academic Alzheimer’s disease clinical trial centers. The ADCS, which was established by NIH, will help facilitate the A4 trial.

The A4 researchers hope that starting treatment with solanezumab before symptoms are present, as well as treating for a longer period of time, will slow cognitive decline and ultimately prevent AD dementia.

After the failure of solanezumab in Lilly’s own Phase 3 studies, and the FDA’s rebuff of the company’s secondary analysis of early stage patients, the A4 study’s choice of solanezumab gives the drug a new lease on life. Meanwhile, Lilly will be continuing its own clinical trial program for solanezumab.

Conclusions

The three clinical trials discussed in this article should allow the scientific and medical community to answer the question as to whether treating patients with pre-AD or very early-stage AD with anti-amyloid MAb drugs can have a positive effect on the course of the disease, and slow or prevent cognitive decline. The studies may also help the scientific and medical community, and the FDA, with issues of evaluation of biomarkers and clinical outcome measures in determining disease prognosis and the efficacy of drug treatments. Given the large size and rapid growth of the at-risk population, finding safe and efficacious disease-modifying preventives and treatments for AD is of increasing urgency.

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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 an initial one-to-one consultation on an issue that is key to your company’s success, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

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Amyloid precursor protein (APP)

As we mentioned in our August 19, 2012 article on Alzheimer’s disease (AD), the results of Phase 3 trials of Lilly’s amyloid-targeting monoclonal antibody (MAb) drug solanezumab, had been expected soon.

On August 24 2012, Lilly announced the top-line results of the two Phase 3, double-blind, placebo-controlled EXPEDITION trials of solanezumab in patients with mild-to-moderate Alzheimer’s disease. The primary endpoints, both cognitive and functional, were not met in either of these trials.

However, a pre-specified secondary analysis of pooled data across both trials showed statistically significant slowing of cognitive decline in the overall study population, and pre-specified secondary subgroup analyses of pooled data across both studies showed a statistically significant slowing of cognitive decline in patients with mild Alzheimer’s disease, but not in patients with moderate Alzheimer’s disease.

These results were reported in a press release.  What was absent was data from the trials. However, the Alzheimer’s Disease Cooperative Study (ADCS), (an academic national research consortium) will present its independent analysis of the data from the EXPEDITION studies at the American Neurological Association (ANA) meeting in Boston on October 8, 2012, and at the Clinical Trials on Alzheimer’s Disease (CTAD) meeting in Monte Carlo, Monaco, on October 30, 2012.

Once again, an amyloid pathway-targeting drug for Alzheimer’s disease that was taken into Phase 3 trials despite Phase 2 results that showed no statistically significant efficacy has failed in Phase 3. Solanezumab joins a list of such failed drugs that includes Myriad Pharmaceuticals’ Flurizan (tarenflurbil), Neurochem’s (now Bellus Health) Alzhemed (3-amino-1-propanesulfonic acid), and as of July 2012, Pfizer/Janssen’s bapineuzumab (“bapi”). Nevertheless, as in the Phase 2 results with bapi, Lilly sees hope for the drug in the results of secondary analyses.

On the day of the Lilly announcement, August 24 2012, Lilly executives and stock analysts turned the results of these trials into something “positive”, as the result of the secondary analysis. This resulted in a one-day 3.4 percent increase in the price of Lilly stock. However, the results of the secondary analysis do not give Lilly any basis for going to the FDA with a New Drug Application (NDA) for solanezumab. Nor do they provide any realistic hope for AD patients, the physicians who treat them, or caregivers of AD patients.

At best, Lilly’s secondary analysis gives rise to a hypothesis–that solanezumab–and presumably other anti-amyloid MAbs–will be effective in treating earlier-stage AD patients, especially those who have not suffered extensive, irreversible brain damage. This is the very same hypothesis that is now being tested by Roche/Genentech in its clinical trials of its anti-amyloid MAb crenezumab, as we discussed in our August 19, 2012 article. Genentech is testing its drug candidate in a Phase 2a trial in a very special population–members of a large Colombian kindred who harbor a mutation in presenilin 1 (PS1) that causes dominant early−onset familial AD.

A News Focus article in the 17 August 2012 issue of Science, written by science writer Greg Miller, PhD, discusses three upcoming clinical trials designed to test the “treat early-stage or presymptomatic AD with anti-amyloid MAbs” hypothesis. One of these studies is the Genentech trial of crenezumab in the extended family in Colombia.

Another of these studies is being conducted in conjunction with the Dominantly Inherited Alzheimer Network (DIAN), a consortium led by researchers at Washington University School of Medicine (St. Louis, MO). This study will include people with mutations in any of the three genes linked to early-stage, dominantly-inherited AD–PS1, PS2, and amyloid precursor protein (APP).

Initial studies, published ahead of print in the July 11 issue of the New England Journal of Medicine (NEJM) looked at changes in biomarkers and in cognitive ability as a function of expected age of AD onset in people with these mutations. Concentrations of amyloid-β1–42 (Aβ42) in the cerebrospinal fluid (CSF) appeared to decline 25 years before expected symptom onset. This decrease may reflect impaired clearance of Aβ42 from the brain, which may be a factor in the amyloid plaque increase that is associated with AD. Amyloid accumulation in the brain was detected 15 years before expected symptom onset. Other biomarkers, as well as cognitive impairment, were also followed in the study published in the NEJM. In the first stage of the actual trial, three drugs (which have not yet been selected) will be tested in this population, and changes in biomarkers and cognitive performance will be followed.

The third study, known as the Anti-Amyloid Treatment of Asymptomatic Alzheimer’s (A4) trial, will involve treating adults without mutations in any of the above three genes, whose brain scans show signs of amyloid accumulation. A4 is thus designed to study prevention of sporadic AD (by far the most common form of the disease). It will enroll 500 people age 70 or older who test positive on a scan of amyloid accumulation in the brain. (This is in contrast to the two trials in subjects with gene mutations, who are typically in their 30s or 40s.) A4 will also have a control arm of 500 amyloid-negative subjects. Amyloid-positive and control subjects will be entered into a three-year double-blind clinical trial that will look at changes in cognition with drug treatment. The A4 researchers [led by  Reisa Sperling, Brigham and Women’s Hospital/Harvard University (Boston, MA), and Paul Aisen, University of California, San Diego] plan to select a drug for testing by December 2012.

If Lilly wishes to test solanezumab in early-stage (or presymptomatic) sporadic AD, it will need to follow a similar methodology to the studies outlined in the new Science article, especially with respect to the use of biomarkers to define “early-stage” AD and to track the effects of the drug. Studies such as the DIAN biomarker study published in the NEJM used the positron emission tomography (PET) ligand Pittsburgh Compound-B (PiB-C11), to image amyloid plaques. However, the use of this compound is limited by the short half-life of carbon-11 (20.4 minutes). A new PET amyloid imaging agent, Amyvid (florbetapir F18 Injection) was developed by Lilly and approved by the FDA in April 2012. This compound contains fluorine-18, which has a half-life of 109.8 minutes. A recent study indicates that Amyvid provides comparable information to PiB-C11. If Lilly wishes to conduct new studies of solanezumab in early-stage or presymptomatic sporadic AD, it may wish to use Amyvid, as suggested in a comment to an August 24, 2012 solanezumab post in Derek Lowe’s blog “In the Pipeline”. However, the FDA, in its press release announcing the approval of Amyvid, warns that increased amyloid plaque content (as detected by Amyvid or Pittsburgh Compound-B) may be present in the brains of patients with non-AD neurologic conditions, and in older people with normal cognition. Thus defining or detecting “early-stage (or presymptomatic) sporadic AD” is difficult.

In any case, for Lilly to follow up on its secondary analyses of the Phase 3 clinical trials of solanezumab will necessitate additional long and expensive clinical trials, with no assurance of success. Lilly executives will need to determine if such a course is worth the risk, or whether it should invest in other R&D efforts that might have a higher probability of success.

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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 click here. We also welcome your comments on this or any other article on this blog.

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