CTLs attacking cancer cells.


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

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

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

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

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

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

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

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

Neoantigen cancer vaccines

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

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

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

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

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

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

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

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

Other neoantigen cancer vaccine companies

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


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

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

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

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

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

PD-1 extracellular domain


As noted in our 2017 Insight Pharma Report, “Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes” the most successful class of immunotherapeutics continues to be that of the checkpoint inhibitors (discussed in Chapter 2 of our report).

Immune checkpoints refer to a large number of inhibitory pathways in the immune system, especially those that block the response of T cells to antigens. Marketed checkpoint inhibitors are all monoclonal antibodies (mAbs). The two leading checkpoint inhibitors, both of which target PD-1, are pembrolizumab (Merck’s Keytruda), and nivolumab, (Bristol-Myers Squibb’s Opdivo), both approved by the FDA in 2014. Of these two, Keytruda has become the market leader during 2016/2017, after a long process of competition with BMS’ Opdivo..

On July 26, 2017, Forbes published a long article by David Shaywitz MD, PhD, entitled “The Startling History Behind Merck’s New Cancer Blockbuster”. This article is a complete history of Keytruda, from discovery through commercialization. As discussed in this article, Roger Perlmutter MD PhD (who became head of Merck Research Labs during the process of development of Keytruda) redirected virtually all work at Merck towards the Keytruda program. He determined that Keytruda was more valuable than the entire rest of Merck’s portfolio put together. Dr. Perlmutter essentially bet both his own career and Merck’s enterprise on the Keytruda program.

Merck has been engaging in an aggressive R&D and commercialization program for Keytruda. In the second quarter of 2017, Keytruda achieved three accelerated approvals and one full approval in the U.S., a recommendation in the EU, and a 180% increase in sales. As of September 2017, Merck has over 550 clinical trials evaluating Keytruda in more than 30 tumor types.

As expected for such an aggressive program, not all of Merck’s efforts have been successful. Three of the company’s combination trials of Keytruda, with Celgene’s Revlimid (lenalidomide) or Pomalyst (pomalidomide) plus dexamethasone in multiple myeloma, have been on hold because of an excess number of deaths in the treatment arm. Merck also had a missed endpoint in recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) in the KEYNOTE-040 trial. Despite this, Keytruda has held onto its accelerated approval for this indication, and other HNSCC trials are ongoing.

Merck’s acquisition of Rigontec

Keytuda has become as much a platform as a product for Merck. This is illustrated by the recent acquisition by Merck of the German company Rigontec for $150 million in cash and another $453 million in milestones payments. According to John Carroll’s Endpoints News, this is an example of how Merck’s Perlmutter likes to augment the work being done around Keytruda with the occasional add-on.

Mr. Carroll refers to the Rigontec deal as a “bolt-on” acquisition. In a “bolt-on” acquisition, a platform company (such as Merck) with the management capabilities, infrastructure and systems that allows for organic or acquisition growth will look for acquisition of smaller companies “that provide complementary services, technology or geographic footprint diversification and can be quickly integrated into the existing management infrastructure.”

Rigontec’s technology platform is based on developing agents that mimic viral infections. Specifically, double-stranded viral RNA is recognized by pattern recognition receptors called RIG-I-like helicases (RLH) that are present in the cytoplasm. Synthetic RLH ligands (such as those being developed by Rigontec) working via RLH initiate a signaling cascade that leads to an antiviral response program, characterized by the production of type I interferon (IFN) and other innate immune response genes. RLH signaling also induces apoptosis in tumor cells. Finally, exposure of CD8alpha+ dendritic cells (DCs) to RLH-activated apoptotic tumor cells induces DC maturation, efficient antigen uptake and cross-presentation of tumor-associated antigens to naive CD8+ T cells.

The exploitation of the RLH system thus constitutes a potential means to activate tumor-specific CD8+ T cells. As discussed in our 2017 Insight Pharma report, checkpoint inhibitors work by reactivating intratumoral T-cells, especially CD8+ cytotoxic T cells. Rigontec’s agents may work to render “cold” tumors inflamed (specifically, with DCs and CD8+ T cells), thus making them more susceptible to the antitumor action of checkpoint inhibitors such as Keytruda. This type of strategy, as discussed in our report, is a major theme of “second wave” immuno-oncology, or “immuno-oncology 2.0.”

However, so far the potential use of Rigontec’s RLH ligands in cancer therapy is based on studies in preclinical tumor models for melanoma, ovarian cancer and pancreatic cancer. Currently, Rigontec has been sponsoring a first-in-humans Phase 1/2 trial of its lead RIG-1 agonist, RGT100, in solid tumors and lymphoma (clinical trial number NCT03065023). This study is designed to assess “safety, tolerability and pharmacokinetics of RGT100 in patients with injectable solid tumor lesions”. In the absence of evidence for clinical efficacy in human cancer patients, the Merck acquisition of Rigontec is a speculative deal. However, upfront Merck’s investment in Rigontec is small, and it gives Merck access to a new mechanism of action, which is complementary to the larger company’s strategy and current pipeline.

Other immunotherapy 2.0 approaches designed to enhance the effectiveness of checkpoint inhibitors

As noted in our 2017 Insight Pharma Report, although checkpoint inhibitors such as Keytruda have achieved spectacular success in treating some patients, they do not work for the majority of patients. Even in the case of melanoma, where checkpoint inhibitors have shown the greatest degree of efficacy, these agents only cure 20% of patients. Therefore, numerous researchers and companies are working to discover and develop complementary “immunotherapy 2.0” treatments to enhance the efficacy of checkpoint inhibitors in various classes of cancer patients. Rigontec’s technology represents only one such approach.

In a recent article published (Sep 7, 2017) in FierceBiotech, writer Arlene Weintraub discussed two companion treatments that might potentially enhance the effectiveness of checkpoint inhibitors. One of these treatments, discovered by scientists at Columbia University Medical Center, is a drug that’s already on the market: pentoxifylline, which is used to increase blood flow in patients with poor circulation. Pentoxifylline’s activity in cancer immunology is based on its inhibition of NF-kB c-Rel.  This results in the inhibition of regulatory T cells (Tregs) in the tumor mcroenvironment. In mouse models, inhibition of c-Rel function by pentoxifylline delayed melanoma growth by impairing Treg-mediated immunosuppression, and thus and potentiated the effects of anti-PD-1 immunotherapy. Adverse effects, such as the induction of autoimmunity that would be expected if the treatment caused global inhibition of Tregs, were not seen. Once again, these studies in mice await confirmation via human clinical trials; such human trials are currently planned.

The other experimental immunotherapy 2.0 approach discussed in Ms. Weintraub’s article involves combining an oncoloytic virus [the modified vaccinia virus Ankara (MVA)] with a checkpoint inhibitor. Once again, the example discussed in this article was in mouse models. As in other immunotherapy 2.0 approaches, the goal is to enable the immune system to recognize the tumor as foreign by injecting the oncolytic virus into it, thus prompting a CD8+ T-cell response. Checkpoint inhibitors might then reactivate the intratumoral T cells, inducing an antitumor response. These studies were also carried out in mouse models, and human trials are planned.

Our report, “Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes”, also includes discussions of the use of oncolytic viruses to boost the anticancer efficacy of checkpoint inhibitors. Some of these approaches (such as studies of combinations of Amgen’s Imlygic (talimogene laherparepvec), an FDA-approved modified oncolytic virus therapy, with checkpoint inhibitors), are already in human studies.

Also in our report is a discussion of treatments being developed by NewLink Genetics designed to modulate the IDO (indoleamine-pyrrole 2,3-dioxygenase) pathway. Such compounds are designed to reverse IDO-mediated immune suppression. IDO pathway inhibitors may complement the use of anti- PD-1and/or anti-PD-L1 checkpoint inhibitors. The same Endpoints News article that discusses the Merck/Rigontec acquisition  also mentions an earlier Merck bolt-on deal—the 2016 acquisition of IOmet. IOmet also works on IDO pathway inhibitors.

More generally, our 2017 Insight Pharma Report contains a wealth of potential immunotherapy 2.0 approaches. Importantly, this includes an “immunotherapy 2.0” approach to cancer vaccine development, which emphasizes combinations of cancer vaccines with checkpoint inhibitors. This may both enhance the efficacy of checkpoint inhibitors, and reverse the high rate of failure of cancer vaccines. Other immunotherapy 2.0 strategies discussed in our report may well make the news over the next several years, in terms of corporate deals and product approvals. Our report is thus well worth reading for those who are interested in the further devlelopment of immuno-oncology.

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


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

Pre-1917 Russian Happy Christmas and Happy New Year card

Pre-1917 Russian Happy Christmas and Happy New Year card

As is their customary practice, both Nature and Science ran end-of-year specials. The Nature special (in their 18 December issue) is entitled “365 days: Nature’s 10. Ten people who mattered this year.” The Science special (in their 19 December issue) is entitled, as usual “2014 Breakthrough of the Year.” As is also usual, there is a section for “Runners Up” to the year’s “Breakthrough”.

From the point of view of a consulting group—and a blog—that focuses on effective drug discovery and development strategies, we were disappointed with both end-of-year specials. Most of the material in these articles was irrelevant to our concerns.

Science chose the Rosetta/Philae comet-chasing mission as the “Breakthrough of the Year”, and its “runners up” included several robotics and space-technology items, as well as new “letters” to the DNA “alphabet” that don’t code for anything.

Nature also focused on comet chasers, robot makers, and space technologists, as well as cosmologist and mathematicians, and a fundraising gimmick—“the ice-bucket challenge”. Moreover, Nature was much too restrictive in titling its article “Ten people who mattered”. Every human being matters!

Nevertheless, these two special sections do contain a few gems that are both relevant to effective drug discovery and development, and are worthy of highlighting as “notable researchers of 2014” and “breakthrough research of 2014”. We discuss these in the remainder of this article.

Suzanne Topalian, M.D.

Suzanne Topalian is one of the researchers profiled in “Nature’s 10”. She is a long-time cancer immunotherapy clinical researcher who began her career in 1985 in the laboratory of cancer immunotherapy pioneer Steven Rosenberg at the National Cancer Institute (Bethesda MD). In the early days of the field, when cancer immunotherapy was scientifically premature, there was a great deal of skepticism that these types of treatments would even work. However, both Dr. Rosenberg and Dr. Topalian persevered in their research.

In 2006, Dr. Topalian moved to Johns Hopkins University (Baltimore, MD) to help launch clinical trials of Medarex/Bristol-Myers Squibb/Ono’s nivolumab, a PD-1 inhibitor. As noted in the Nature article, her work “led to a landmark publication in 2012 showing that nivolumab produced dramatic responses not only in some people with advanced melanoma but also in those with lung cancer [specifically, non–small-cell lung cancer, NSCLC].” We also discussed that publication on the Biopharmconsortium Blog, and in our recently published book-length Insight Pharma Report, Cancer Immunotherapy: immune checkpoint inhibitors, cancer vaccines, and adoptive T-cell therapies. Our report also includes discussions of Dr. Rosenberg’s more recent work in cellular immunotherapy.

As discussed in our report, nivolumab was approved in Japan as Ono’s Opdivo in July 2014 for treatment of unresectable melanoma, and a competitive PD-1 inhibitor, pembrolizumab (Merck’s Keytruda) was approved in the United States for advanced melanoma on September 5, 2014. More recently, on December 22, 2014, the FDA also approved nivolumab (BMS’ Opdivo) for advanced melanoma in the U.S. There are thus now two FDA-approved PD-1 inhibitors [in addition to the CTLA-4 inhibitor ipilimumab (BMS’ Yervoy)] available for treatment of advanced melanoma in the U.S.

Meanwhile, researchers continue to test both nivolumab and pembrolizumab for treatment of NSCLC and other cancers. And some analysts project that both of these agents are likely to be approved by the FDA for treatment of various populations of patients with NSCLC before the middle of 2015. Researchers are also testing combination therapies that include nivolumab or pembrolizumab in various cancers. And clinical trials of Genentech/Roche’s PD-L1 blocking agent MPDL3280A are also in progress.

Science’s 2013 Breakthrough of the Year was cancer immunotherapy, as we highlighted in our New Year’s 2014 blog article. Science could not make cancer immunotherapy the Breakthrough of the Year for 2014, too. Thus it chose to give physical scientists a turn in the limelight by highlighting the comet-chasing mission instead. Nevertheless, 2014 was the year in which cancer immunotherapy demonstrated its maturity by the regulatory approval of the two most advanced checkpoint inhibitor agents, pembrolizumab and nivolumab.

Implications for patients with terminal cancers

The clinically-promising results of cancer immunotherapy in a wide variety of cancers, coupled with the very large numbers of clinical trials in progress in this area, has also changed the situation for patients who have terminal cancers. Researchers who are conducting clinical trials of immunotherapies for these cancers are actively recruiting patients, of whom there are limited numbers at any one time. For example, there are now numerous clinical trials—mainly of immunotherapies—in pancreatic cancer, and most of these trials are recruiting patients. There are also active clinical trials of promising immunotherapies in the brain tumor glioblastoma. These are only two of many examples.

Recently, a 29-year-old woman with terminal glioblastoma ended her life using Oregon’s physician-assisted suicide law. Prior to her suicide, she became an advocate for “terminally ill patients who want to end their own lives”. We, however, are advocating that patients with glioblastoma and other types of terminal cancer for which there are promising immunotherapies seek out clinical trials that are actively recruiting patients. There is the possibility that some of these patients will receive treatments that will result in regression of their tumors or long-term remissions. (See, for example, the case highlighted in our September 16, 2014 blog article. There are many other such cases.) And it is highly likely that patients who participate in these trials will help researchers to learn how to better treat cancers that are now considered “incurable” or “terminal”, and thus help patients who contract these diseases in the future. From our point of view, that is a lot better than taking one’s own life via assisted suicide, and/or becoming an euthanasia advocate.

Masayo Takahashi, M.D., Ph.D.

Another researcher profiled in “Nature’s 10” is Masayo Takahashi, an ophthalmologist at the RIKEN Center for Developmental Biology (CDB) in Kobe, Japan who has been carrying out pioneering human stem cell clinical studies. We also discussed Dr. Takahashi’s research in our March 14, 2013 article on this blog.

At the time of our article, Dr. Takahashi and her colleagues planned to submit an application to the Japanese health ministry for a clinical study of induced pluripotent stem cell (iPS)-derived cells, which would constitute the first human study of such cells. They planned to treat approximately six people with severe age-related macular degeneration (AMD). The researchers planned to take an upper arm skin sample the size of a peppercorn, and transform the cells from this sample into iPS cells by using specific proteins. They were then to add other factors to induce differentiation of the iPS cells into retinal cells. Then a small sheet of these retinal cells were to be placed under the damaged area of the retina, where they were expected to grow and repair the damaged retinal pigment epithelium (RPE). Although the researchers would like to demonstrate efficacy of this treatment, the main focus of the initial studies was to be on safety.

According to the “Nature’s 10” article, such an autologous iPS-derived implant was transplanted into the back of a the damaged retina of one patient in September 2014. This patient, a woman in her 70s, had already lost most of her vision, and the treatment is unlikely to restore it. However, Dr. Takahashi and her colleagues are determining whether the transplant is safe and prevents further retinal deterioration. So far, everything has gone smoothly, and the transplant appears to have retained its integrity. However, the researchers will not reveal whether the study has been a success until a year after the transplantation.

The “Nature’s 10” article discusses how this technology might be moved forward into clinical use if the initial study is successful. It also discusses how Dr. Takahashi has been carrying her research forward in the face of a major setback that has plagued stem cell research at the CDB in 2014, as the result of the withdrawal of two once highly-regarded papers and the suicide of one of their authors.

Generation of insulin-producing human pancreatic β cells from embryonic stem (ES) cells or iPS

Another stem cell-related item, which was covered in Science’s end-of-2014 “Runners Up” article, concerned the in vitro generation of human pancreatic β cells from embryonic stem (ES) cells or iPS. For over a decade, researchers have been attempting to accomplish this feat, in order to have access to autologous β cells to treat type 1 diabetes, in which an autoimmune attack destroys a patient’s own β cells. In vitro generated β cells might also be used to screen for drugs that can improve β cell function, survival, and/or proliferation in patients with type 2 diabetes.

As reported in the Science article, two research groups—one led by Douglas A. Melton, Ph.D. (Harvard Stem Cell Institute, Cambridge, MA), and the other by Alireza Rezania, Ph.D. at BetaLogics Venture, a division of Janssen Research & Development, LLC.–developed protocols to produce unlimited quantities of β cells, in the first case from IPS cells, and in the other from ES cells.

However, in order to use the β cells to treat type 1 diabetes patients, researchers need to develop means (for example, some type of encapsulation) to protect the cells from the autoimmune reaction that killed patients’ own natural β cells in the first place. For example, Dr. Melton is collaborating with the laboratory of Daniel Anderson, Ph.D. (MIT Koch Institute for Integrative Cancer Research). Dr. Anderson and his colleagues have developed a chemically modified alginate that can be used to coat and protects clusters of β cells, thus forming artificial islets. Dr. Melton estimates that such implants would be about the size of a credit card.

The 2014 Boston biotech IPO boom

Meanwhile, the Boston area biotechnology community has seen a boom in young companies holding their initial public offerings (IPOs). 17 such companies were listed in a December 24 article in the Boston Business Journal. Among these companies are three that have been covered in the Biopharmconsortium Blog—Zafgen, Dicerna, and Sage Therapeutics.

We hope that 2015 will see at least the level of key discoveries, drug approvals, and financings seen in 2014.

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.

T cells attached to tumor cell. Source: MSKCC. http://bit.ly/1uPr5nl

T cells attached to tumor cell. Source: MSKCC. http://bit.ly/1uPr5nl

On September 9, 2014, Cambridge Healthtech Institute’s (CHI’s) Insight Pharma Reports announced the publication of a new book-length report, Cancer Immunotherapy: Immune Checkpoint Inhibitors, Cancer Vaccines, and Adoptive T-cell Therapies, by Allan B. Haberman, Ph.D.

As attested by the torrent of recent news, cancer immunotherapy is a “hot”, fast-moving field. For example:

  • On September 5, 2014, the FDA granted accelerated approval to the PD-1 inhibitor pembrolizumab (Merck’s Keytruda, also known as MK-3475) for treatment of advanced melanoma. This approval was granted nearly two months ahead of the agency’s own deadline. Pembrolizumab is the first PD-1 inhibitor to reach the U.S. market.
  • On May 8, 2014, the New York Times published an article about a woman in her 40’s who was treated with adoptive immunotherapy with autologous T cells to treat her cancer, metastatic cholangiocarcinoma (bile-duct cancer). This deadly cancer typically kills the patient in a matter of months. However, as a result of this treatment, the patient lived for over 2 years, with good quality of life, and is still alive today.

These and other recent news articles and scientific publications attest to the rapid progress of cancer immunotherapy, a field that only a few years ago was considered to be impracticable.

Our report focuses on the three principal types of therapeutics that have become the major focuses of research and development in immuno-oncology in recent years:

  • Checkpoint inhibitors
  • Therapeutic anticancer vaccines
  • Adoptive cellular immunotherapy

The discussions of these three types of therapeutics are coupled with an in-depth introduction and history as well as data for market outlook.

Also featured in this report are exclusive interviews with the following leaders in cancer immunotherapy:

  • Adil Daud, MD, Clinical Professor, Department of Medicine (Hematology/Oncology), University of California at San Francisco (UCSF); Director, Melanoma Clinical Research, UCSF Helen Diller Family Comprehensive Cancer Center.
  • Matthew Lehman, Chief Executive Officer, Prima BioMed (a therapeutic cancer vaccine company with headquarters in Sydney, Australia).
  • Marcela Maus, MD, PhD, Director of Translational Medicine and Early Clinical Development, Translational Research Program, Abramson Cancer Center, University of Pennsylvania in Philadelphia.

The report also includes the results and an analysis of a survey of individuals working in immuno-oncology R&D, conducted by Insight Pharma Reports in conjunction with this report. The survey focuses on market outlook, and portrays industry opinions and perspectives.

Our report is an in-depth discussion of cancer immunotherapy, an important new modality of cancer treatment that may be used to treat as many as 60% of cases of advanced cancer by the late 2010s/early 2020s. It includes updated information from the 2014 ASCO (American Society of Clinical Oncology) and AACR (American Association for Cancer Research) meetings. The report is designed to enable you to understand current and future developments in immuno-oncology. 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 Cancer Immunotherapy: Immune Checkpoint Inhibitors, Cancer Vaccines, and Adoptive T-cell Therapies, or to order it, see the 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.

Ubiquitin pathway. Source: Rogerdodd, English language Wikipedia

Ubiquitin pathway. Source: Rogerdodd, English language Wikipedia

On April 1, 2014, Forma Therapeutics (Watertown MA) announced that it had entered into an expanded strategic collaboration with Celgene (Summit, NJ).

Under the new agreement, Forma has received an upfront cash payment of $225 million. The initial collaboration between the two companies under the new agreement will be for 3 1⁄2 years. Celgene will also have the option to enter into up to two additional collaborations with terms of two years each for additional payments totaling approximately $375 million. Depending on the success of the collaborations and if Celgene elects to enter all three collaborations, the combined duration of the three collaborations may be at least 7 1⁄2 years.

Under the terms of the new agreement, Forma will control projects from the research stage through Phase 1 clinical trials. For programs selected for licensing, Celgene will take over clinical development from Phase 2 to commercialization. Forma will retain U.S. rights to these products, and Celgene will have the rights to the products outside of the U.S. For products not licensed to Celgene, FORMA will maintain worldwide rights.

During the term of the third collaboration, Celgene will have the exclusive option to acquire Forma, including the U.S. rights to all licensed programs, and worldwide rights to other wholly owned programs within Forma at that time.

The April 2013 agreement between Forma and Celgene

The new collaboration between Forma and Celgene builds on an earlier agreement between the two companies. On April 29, 2013, the two companies entered into a collaboration aimed at discovery, development, and commercialization of drug candidates to modulate targets involved in protein homeostasis.

Protein homeostasis, also known as proteostasis, involves a tightly regulated network of pathways controlling the biogenesis, folding, transport and degradation of proteins. The ubiquitin pathway (illustrated in the figure above) is one of these pathways. We recently discussed how the ubiquitin pathway is involved in the mechanism of action of thalidomide and lenalidomide (Celgene’s Thalomid and Revlimid).

Targeting protein homeostasis has application to discovery and development of drugs for oncology, neurodegenerative disease, and other disorders. However, the April 2013 Forma/Celgene agreement focused on cancer. Under that agreement, Forma received an undisclosed upfront payment. Upon licensing of preclinical drug candidates by Celgene, Forma was to be eligible to receive up to $200 million in research and early development payments. FORMA was also to be eligible to receive $315 million in potential payments based upon development, regulatory and sales objectives for the first ex-U.S. license, as well as  up to a maximum of $430 million per program for further licensed products, in addition to post-sales royalties.

On October 8, 2013, Forma announced that it had successfully met the undisclosed first objective under its April 2013 strategic collaboration agreement with Celgene. This triggered an undisclosed payment to Forma. Progress in the April 2013 collaboration was an important basis for Celgene’s decision to enter into a new, broader collaboration with Forma a year later.

The scope of the new April 2014 Forma/Celgene collaboration

Unlike the April 2013 agreement, the April 2014 agreement between Forma and Celgene is not limited to protein homeostasis, or to oncology. The goal of the new collaboration is to “comprehensively evaluate emerging target families for which Forma’s platform has exceptional strength” over “broad areas of chemistry and biology”.  The expanded collaboration will thus involve discovery and development of compounds to address a broad range of target families and of therapeutic areas.

According to Celgene’s Thomas Daniel, M.D. (President, Global Research and Early Development), Celgene’s motivation for signing the new agreement is based not only on the early success of the existing Forma/Celgene collaboration, but also on “emerging evidence of the power of Forma’s platform to generate unique chemical matter across important emerging target families”.

According to Forma’s President and CEO, Steven Tregay, Ph.D., the new collaboration with Cegene enables Forma to maintain its autonomy in defining its research strategy and conducting discovery through early clinical development. It also aligns Forma with Celgene’s key strengths in hematology and in inflammatory diseases.

Forma Therapeutics in Haberman Associates publications

We have been following Forma on the the Biopharmconsortium Blog since July 2011. At that time, I was a speaker at Hanson Wade’s World Drug Targets Summit (Cambridge, MA). At that meeting, Mark Tebbe, Ph.D. (then Vice President, Medicinal and Computational Chemistry at Forma) was also a speaker. At the conference, Dr. Tebbe discussed FORMA’s technology platforms, which are designed to be enabling technologies for discovery of small-molecule drugs to address challenging targets such as protein-protein interactions (PPIs).

In particular, Dr. Tebbe discussed Forma’s Computational Solvent Mapping (CS-Mapping) platform, which enables company researchers to interrogate PPIs in intracellular environments, to define hot spots on the protein surfaces that might constitute targets for small-molecule drugs. FORMA has been combining CS-Mapping technology with its chemistry technologies (e.g., structure guided drug discovery, diversity orientated synthesis) for use in drug discovery.

We also discussed Forma’s earlier fundraising successes as of January 2012, and cited Forma as a “built to last” research-stage platform company in an interview for Chemical & Engineering News (C&EN).

Finally, we discussed Forma and its technology platform in our book-length report, Advances in the Discovery of Protein-Protein Interaction Modulators, published by Informa’s Scrip Insights in 2012. (See also our April 25, 2012 blog article.)

In our report, we discussed Forma as a company that employs “second-generation technologies” for the discovery of small-molecule PPI modulators. This refers to a suite of technologies designed to overcome the hurdles that stand in the way of the accelerated and systematic discovery and development of PPI modulators. Such technologies are necessary to make targeting of PPIs a viable field.

Forma’s website now has a brief explanation of its drug discovery engine, as it is applied to targeting PPIs. This includes links to web pages describing:

Our 2012 book-length report discusses technologies of these types, as applied to discovery of PPI modulators, in greater detail than the Forma website.

According to Dr. Daniel: “Progress in our existing [protein homeostasis] collaboration, coupled with emerging evidence of the power of FORMA’s platform to generate unique chemical matter across important emerging target families” led Celgene to enter into its new, expanded collaboration with Forma in April 2014. This suggests that Celgene is especially impressed by Forma’s chemistry and chemical biology platforms. it also suggests that chemistry technology platforms developed to address PPIs may be applicable to areas of drug discovery beyond PPIs as well.

Concluding remarks

Despite the enthusiasm for Forma and its drug discovery engine shown by Celgene, Forma’s other partners, and various industry experts, it must be remembered that Forma is still a research-stage company. The company has not one lone drug candidate in the clinic, let alone achieving proof-of-concept in humans. It is clinical proof-of-concept, followed by Phase 3 success and approval and marketing of the resulting drugs, that is the “proof of the pudding” of a company’s drug discovery and development efforts.

We await the achievement of such clinical milestones by Forma Therapeutics.

From a business strategy point of view, we have discussed Forma’s efforts to build a stand-alone, independent company for the long term in this blog and elsewhere. Now Forma has entered into an agreement with Celgene that might—in around 7-10 years—result in Forma’s acquisition. This would seem to contradict Forma’s “built to last” strategy.

However, in the business environment that has prevailed over the past several years, several established independent biotech companies, notably Genentech and Genzyme, have been acquired by larger companies. Even several Big Pharmas (e.g., Schering-Plough and Wyeth) have been acquired.

Nevertheless, we do not know what the business environment in the biotech/pharma industry will be like in 7-10 years, despite the efforts of strategists to predict it. And Celgene might forgo its option to acquire Forma, for any number of reasons. So the outlook for Forma’s status as an independent or an acquired company (which also depends on its success in developing drugs) is uncertain.


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