Source: Medical Progress Today 12/14/12 http://bit.ly/1sPO1WU

In our September 16, 2014 article on this blog, we announced the publication by Cambridge Healthtech Institute’s (CHI’s) Insight Pharma Reports 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 we said in that blog article, “cancer immunotherapy is a ‘hot’, fast-moving field”. Thus—inevitably—in the short time since the publication of our report, a great deal of late-breaking news has come in.

This article is a discussion of several key late-breaking news items, which were not published in the report.

Pricing of checkpoint inhibitor agents

As discussed in the report, two PD-1 inhibitors have been recently approved. Bristol-Myers Squibb (BMS)/Ono’s nivolumab was approved in Japan (where it is know by the brand name Opdivo) in July 2014 for treatment of unresectable melanoma. Pembrolizumab (Merck’s Keytruda) was approved in the U.S. for treatment of advanced melanoma on September 5, 2014. The very first checkpoint inhibitor to reach the market, the CTLA-4 inhibitor ipilimumab (Medarex/BMS’s Yervoy), was approved in the U.S. in 2011.

At the same time as the news of the approval of the PD-1 inhibitors nivolumab and pembrolizumab came out, information on the pricing of these agents also became available. However, because of the need to complete the report for publication, there was no time to discuss the issue of pricing adequately.

As discussed in a September 4, 2014 article in FiercePharma, the cost of nivolumab in Japan (according to the Wall Street Journal) is $143,000. According to the FierceBiotech article, this was greater than the introductory price for any other cancer drug, especially in Japan, where prices tend to be somewhat lower than in the U.S.

Meanwhile, as reported in a September 4, 2014 article in FierceBiotech, the cost of pembrolizumab in the U.S. will be $12,500 a month, or $150,000 a year.

For comparison, the launch price of BMS’ ipilimumab was $120,000. As we discussed in the report, the PD-1 inhibitors nivolumab and pembrolizumab—as seen in early clinical trials—appear to be more efficacious and have fewer adverse effects in treatment of melanoma.

As discussed in our report, checkpoint inhibitors such as ipilimumab, nivolumab and pembrolizumab are eventually likely to be used in combination with other drugs, including other immuno-oncology drugs, targeted therapies, and others. The price per month or per year of these potentially life-saving and at least in some cases curative combination therapies may thus be expected to go still higher. However, if cancers are pushed into long-term remission or even cure, then it might be possible to discontinue treatment with these expensive drug combinations. In such cases, the cost of treatment may even be less than current therapeutic regimens.

There are no analyses of the costs of specific immunotherapy drugs or cellular therapies in our report. However, we do discuss the issue of drug costs in the survey and interviews that are part of the report.

The issue of the costs of expensive drugs for life-threatening cancers is under discussion in the cancer community. For example, the American Society of Clinical Oncology (ASCO) has initiated an effort to rate oncology drugs not only on their efficacy and adverse effects, but also on their prices. ASCO’s concern is that pricing be related to the therapeutic value of drugs. And commentators such as Peter Bach, MD, MAPP (the Director of the Memorial Sloan Kettering Cancer Center’s Center for Health Policy and Outcomes) have been weighing in with their analyses. As additional immunotherapy drugs and cellular therapies reach the market, these discussions will certainly continue.

The Bristol-Myers Squibb-Merck lawsuit over PD-1 inhibitors

Another late-breaking news item that came out at the time of the publication of our report is the lawsuit between BMS and Merck over PD-1 inhibitors. Specifically, as soon as Merck gained FDA approval for pembrolizumab, BMS and its Japanese partner Ono sued Merck for patent infringement.

The patent in question is U.S. patent number 8,728,474. It was filed on December 2, 2010, granted to Ono on May 20, 2014, and licensed to BMS. The patent covers the use of anti-PD-1 antibodies to treat cancer. According to BMS and Ono’s claims, Merck started developing pembrolizumab after BMS and Ono had already filed their patent and were putting it into practice by developing their own PD-1 inhibitor, nivolumab.

The lawsuit asks for damages, and for a ruling that Merck is infringing the BMS/Ono PD-1 patent. Such a ruling may mean that BMS and Ono are owed royalties on sales of all rival PD-1 drugs, not just Merck’s. BMS/Ono and Merck are involved in parallel litigation in Europe.

Merck acknowledges Ono’s method patent, but says that it is invalid. Merck also said the lawsuit will not interfere with the U.S. launch of pembrolizumab.

We shall have to watch the proceedings in the U.S. District Court for the District of Delaware to see the outcome of this case. Although this lawsuit was not discussed in our report, the report does include a discussion of the fierce race between PD-1 inhibitor developers Merck and BMS to be the first to market, and to gain the largest market share. The lawsuit is clearly one element in this race.

Merck Serono discontinues development of the cancer vaccine tecemotide

On September 18, 2014, Merck KGaA (Darmstadt, Germany; also known as Merck Serono and EMD Serono) announced that it has discontinued development of the cancer vaccine tecemotide. Tecemotide is a peptide vaccine that was formerly known as Stimuvax. It was originally developed by Oncothyreon (Seattle, WA) and licensed to Merck Serono in 2007.

We covered tecemotide in our report, both as an example of a cancer vaccine that had failed in Phase 3 clinical trials, and as an example of a vaccine that was nevertheless still under development. As discussed in our report, in a Phase 3 trial known as START in non-small cell lung cancer (NSCLC) patients, researchers found no significant difference in overall survival between administration of tecemotide or placebo. However, a subsequent analysis suggested that there was a statistically significant survival advantage for tecemotide compared with placebo in a pre-defined subset of patients. Based on these results, Merck Serono began a second Phase 3 trial in that subset.

However, as the result of a failure in a Phase 3 trial in Japan sponsored by Oncothyreon (reported on August 19, 2014), Merck Serono decided to discontinue development.

As stated by Merck Serono’s Executive Vice President and Global Head of R&D Luciano Rossetti, “While the data from the exploratory subgroup analysis in the START trial generated a reasonable hypothesis to warrant additional study, the results of the recent trial in Japanese patients decreased the probability of current studies to reach their goals.”

As we discussed in our report, the cancer vaccine field has been rife with clinical failures—from its beginnings in the 1990s to the present day. This has especially included late-stage failures, not only that of Merck Serono’s tecemotide, but also, for example, GlaxoSmithKline’s (GSKs) MAGE-A3 vaccine. Only one anticancer vaccine—sipuleucel-T (Dendreon’s Provenge) for treatment of metastatic castration-resistant prostate cancer—has ever reached the market, and its therapeutic effects appear to be minimal.

Despite these poor results, researchers and companies persist in their efforts to develop cancer vaccines. Our report discusses why cancer vaccine R&D continues despite the overwhelming history of failure, the hypothesized reasons for these failures, and what researchers and companies can do and are doing to attempt to obtain better results.

Conclusions

As a fast-moving, important field, cancer immunotherapy will continue to generate scientific, medical, and market news. There will continue to be periodic meetings, such as the 2014 European Society for Medical Oncology (EMSO) meeting (September 26-30, Madrid, Spain), in which positive results of small, early-stage trials of several checkpoint inhibitors were presented. Our report—an in-depth discussion of cancer immunotherapy—can enable you to understand such future developments, as well as current ones. It is also designed to inform the decisions of leaders in companies and in academia that are involved in 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.

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.

Agios Kirykos, Ikaria, Greece. Source: http://commons.wikimedia.org/wiki/File:Agios_Kirikos,_Ikaria.jpg

Because of being very busy with other projects, we have not posted an article on this blog since April 10, 2014. However, the Biopharmconsortium Blog is still here. More importantly, Haberman Associates biotech/pharma consulting is still here, and we’re still accepting new clients.

Thanks to the many readers who have continued to follow our website and blog during our blogging hiatus, and who have linked to our blog on Twitter and on other social media.

During the hiatus, several of the companies that we have been following on our blog have been progressing. Over the next several months, we shall be blogging about some of these companies, as well as about other notable industry events that have occurred in recent weeks and that will occur during the remainder of 2014.

The first company that we are writing about is cancer metabolism specialist Agios Pharmaceuticals (Cambridge, MA). Our most recent three articles about Agios on this blog are:

• https://biopharmconsortium.com/blog/2012/12/28/haberman-associates-in-chemical-engineering-news-cen-article-on-agios-pharmaceuticals/
• https://biopharmconsortium.com/blog/2013/06/17/agios-pharmaceuticals-files-for-an-ipo/
• https://biopharmconsortium.com/agios-pharma-becomes-a-clinical-stage-company

In our September 23, 2013 article, we noted that Agios had initiated its first clinical study—a Phase 1 clinical trial of AG-221 in patients with advanced hematologic malignancies bearing an isocitrate dehydrogenase 2 (IDH2) mutation. AG-221 is a first-in-class, orally available, selective, potent inhibitor of the mutated IDH2 protein. It is thus a targeted (and personalized) therapy for patients with cancers with an IDH2 mutation.

On June 14, 2014, Agios reported on new clinical data in its ongoing Phase 1 trial of AG-221, which was presented at the 19th Congress of the European Hematology Association (EHA) in Milan, Italy by Stéphane de Botton, M.D. (Institut de Cancérologie Gustave Roussy, Villejuif, France).

The presentation reported on the results of AG-221 treatment of 35 patients with IDH2 mutation positive hematologic malignancies. The researchers observed objective responses in 14 out of 25 evaluable patients, and stable disease in an additional 5 patients. Six patients experienced complete remissions which lasted from one to four months, and are still ongoing. AG-221 has shown favorable pharmacokinetics at all doses tested, with large reductions in serum levels of the oncometabolite 2-hydroxyglutarate (2HG). AG-221 was also well tolerated.

The new data confirms and builds upon previously results. The favorable safety and efficacy data supports Agios’ plan to initiate four expansion cohorts in the second half of 2014. Agios also expects to submit additional data from the ongoing Phase 1 trial for presentation at a later scientific meeting in 2014.

Meanwhile, as announced on June 13, 2014, Agios’ partner Celgene exercised its option to an exclusive worldwide license for AG-221. It exercised this option early, based on the Phase 1 data generated so far.

On June 16, 2014, Agios announced that the FDA granted orphan drug designation for AG-221 for treatment of patients with acute myelogenous leukemia (AML). On August 13, 2014, the FDA also granted Fast Track designation to AG-221 for the treatment of patients with AML that carry an IDH2 mutation.

Thus development of Agios’ lead compound, AG-221, continues to progress. Several other Agios R&D programs are also progressing, as detailed in the company’s report for the second quarter of 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.

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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