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

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

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 July 4, 2014, Bristol-Myers Squibb’s rival PD-1 inhibitor nivolumab was approved for treatment of advanced melanoma in Japan, where it will be marketed as Opdivo by Ono Pharmaceuticals. Nivolumab is the first PD-1 inhibitor to reach the Asian 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

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:

• CS-Map technology
• Forma’s compound libraries, based in part on diversity-oriented synthesis
• Cell-based high-throughput screening (HTS) technologies
• Forma’s high speed solution phase parallel synthesis and purification platform. This platform provides Forma with the potential to perform medicinal chemistry at an extremely accelerated pace.

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.

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.

Transthyretin protein structure

Not so long ago, the once-promising field of RNA interference (RNAi)-based drugs was on the downswing. This was documented in our August 22, 2011 article on this blog, entitled “The Big Pharma Retreat From RNAi Therapeutics Continues”. That article discussed the retreat from RNAi drugs by such Big Pharma companies as Merck, Roche, and Pfizer. In our March 30, 2012 blog article, we also mentioned leading RNAi company Alnylam’s (Cambridge, MA) January 20, 2012 downsizing. This restructuring was made necessary by Alnylam’s inability to continue capturing major Big Phama licensing and R&D deals, as it had once done.

As we discussed in our August 22, 2011 article, the therapeutic RNAi (and microRNA) field represented an early-stage area of science and technology, which may well be technologically premature. This level of scientific prematurity was comparable to that of the monoclonal antibody (MAb) drug field in the 1980s. Big Pharmas did not have the patience to continue with the RNAi drug programs that they started.

In that article, we cited an editorial by oligonucleotide therapeutics leader Arthur Krieg, M.D. This editorial discussed the issues of therapeutic RNAi’s scientific prematurity, but predicted a rapid upswing of the field once the main bottleneck–oligonucleotide drug delivery–had been validated.

The January 2014 Alnylam-Genzyme/Sanofi deal

Now–as of January 2014–there is much evidence that the therapeutic RNAi field is indeed coming back. This is especially true for Alnylam. On January 13, 2014, it was announced that Genzyme (since 2011 the rare disease unit of Sanofi) invested $700 million in Alnylam’s stock. Alnylam called this deal “transformational” for both Alnylam and the RNAi therapeutics field.

Genzyme had previously been a partner in developing Alnylam’s lead product patisiran (ALN-TTR02) for the treatment of transthyretin-mediated amyloidosis (ATTR). [ATTR is a rare inherited, debilitating, and often fatal disease caused by mutations in the transthyretin (TTR) gene.] Under the new agreement, Genzyme will gain marketing rights to patisiran everywhere except North America and Western Europe upon its successful completion of clinical trials and approval by regulatory agencies. Genzyme will also codevelop ALN-TTRsc, a subcutaneously-delivered formulation of patisiran. Intravenously-delivered patisiran is now in Phase 3 trials for a form of ATTR known as familial amyloidotic polyneuropathy (FAP), and ALN-TTRsc is in Phase 2 trials for a form of ATTR known as familial amyloidotic cardiomyopathy (FAC).

The Alnylam/Genzyme deal will also cover any drugs in Alnylam’s pipeline that achieve proof-of-concept before the end of 2019. Genzyme will have the option to development and commercialize these drugs outside of North America and Western Europe.

On the same day as the announcement of the new Alnylam/Genzyme deal, Alnylam acquired Merck’s RNAi program, which consists of what is left of the former  Sirna Therapeutics, for an upfront payment of $175 million in cash and stock. (This compares to the $1.1 billion that Merck paid for Sirna in 2006.) Alnylam will receive Merck’s RNAi intellectual property, certain preclinical drug candidates, and rights to Sirna/Merck’s RNAi delivery platform. Depending on the progress of any of Sirna/Merck’s products in development, Alnylam may also pay Merck up to $105 million in milestone payments per product.

Alnylam’s Phase 1 clinical studies with its ALN-TTR RNAi drugs

In August 2013, Alnylam and its collaborators published the results of their Phase 1 clinical trials of ALN-TTR01 and ALN-TTR02 (patisiran) in the New England Journal of Medicine. At the same time, Alnylam published a press release on this paper.

ALN-TTR01 and ALN-TTR02 contain exactly the same oligonucleotide molecule, which is designed to inhibit expression of the gene for TTR via RNA interference. They differ in that ALN-TTR01 is encapsulated in the first-generation version of liponanoparticle (LNP) carriers, and ALN-TTR02 is encapsulated in second-generation LNP carriers. Both types of LNP carriers are based on technology that is owned by Tekmira Pharmaceuticals (Vancouver, British Columbia, Canada) and licensed to Alnylam.

Tekmira’s LNP technology was formerly known as stable nucleic acid-lipid particle (SNALP) technology. Alnylam and Tekmira have had a longstanding history of collaboration involving SNALP/LNP technology, as described in our 2010 book-length report, RNAi Therapeutics: Second-Generation Candidates Build Momentum, published by Cambridge Healthtech Institute. Although the ownership of the intellectual property relating to SNALP/LNP technology had been the subject of litigation between the two companies, these disputes were settled in an agreement dated November 12, 2012. On December 16, 2013, Alnylam made a milestone payment of $5 million to Tekmira upon initiation of Phase 3 clinical trials of patisiran.

LNP-encapsulated oligonucleotides accumulate in the liver, which is the site of expression, synthesis, and secretion of TTR. As we discussed both in our book-length RNAi report, and in an article on this blog, delivery of oligonucleotide drugs (including “naked” oligonucleotides and LNP-encapsulated ones) to the liver is easier than targeting most other internal organs and tissues. The is a major reason for the emphasis on liver-targeting drugs by Alnylam and other therapeutic oligonucleotide companies.

To summarize the published report, each of the two formulations was studied in a single-dose, placebo-controlled Phase 1 trial. Both formulations showed rapid, dose-dependent, and durable RNAi-mediated reduction in blood TTR levels. (Both mutant and wild-type TTR production was suppressed by these drugs.)

ALN-TTR02 was much more potent than ALN-TTR01. Specifically, ALN-TTR01 at a dose of 1.0 milligram per kilogram, gave a mean reduction in TTR at day 7 of 38%, as compared with placebo. ALN-TTR02 gave mean reductions at doses from 0.15 to 0.3 milligrams per kilogram ranging from 82.3% to 86.8% at 7 days, with reductions of 56.6 to 67.1% at 28 days. The main adverse effects seen in the study were mild-to-moderate acute infusion reactions. These were observed in 20.8% of subjects receiving ALN-TTR01 and in 7.7% (one patient) of subjects receiving ALN-TTR02. These adverse effects could be managed by slowing the infusion rate. There were no significant increases in liver function test parameters in these studies.

The results of these studies have established proof-of-concept in humans that Alnylam’s TTR RNAi therapies can successfully target messenger RNA (mRNA) transcribed from the disease-causing gene for TTR. Alnylam also said in its press release that these results constitute “the most robust proof of concept for RNAi therapy in man to date”, and that they demonstrate proof-of-concept not only for RNAi therapeutics that target TTR, but also for therapeutic RNAi targeting of liver-expressed genes in general. They also note that this represents the first time that clinical results with an RNAi therapeutic have been published in the New England Journal of Medicine.

Other recent RNAi therapeutics deals, and the resurgence of the therapeutic RNAi field

The January 2014 Alnylam/Genzyme/Sanofi agreement is not the only therapeutic RNAi deal that has been making the news in 2013 and 2014. On July 31, 2013, Dicerna Pharmaceuticals (Watertown, MA) secured $60 million in an oversubscribed Series C venture financing. These monies will be used to conduct Phase 1 clinical trials of Dicerna’s experimental RNAi therapies for hepatocellular carcinoma and for unspecified genetically-defined targets in the liver. So far, Dicerna has raised a total of $110 million in venture capital.

Dicerna’s RNAi therapeutics are based on its proprietary Dicer substrate siRNA technology, and its EnCore lipid nanoparticle delivery vehicles.

On January 9, 2014, Santaris Pharma A/S (Hørsholm, Denmark) announced that it had signed a worldwide strategic alliance with Roche to discover and develop novel RNA-targeted medicines in several disease areas, using Santaris’ proprietary Locked Nucleic Acid (LNA) technology platform. Santaris will receive an upfront cash payment of $10 million, and a potential $138M in milestone payments. On January 10, 2014, Santaris announced another agreement to develop RNA-targeted medicines, this time with GlaxoSmithKline. Financial details of the agreement were not disclosed.

As in the case of Alnylam, we discussed Dicerna’s and Santaris’ technology platforms in our 2010 book-length report, RNAi Therapeutics: Second-Generation Candidates Build Momentum.

A January 15, 2014 FierceBiotech article reported that RNAi therapeutic deals were a hot topic at the 2014 J.P. Morgan Healthcare Conference in San Francisco, CA. This is a sign of the comeback of the therapeutic RNAi field, and of the return of interest by Big Pharma and by venture capitalists in RNAi drug development.

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