Biopharmconsortium Blog

Expert commentary from Haberman Associates biotechnology and pharmaceutical consulting.

Monthly Archives: January 2014

RNAi therapeutics stage a comeback

Transthyretin protein structure

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.


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.

Can Merck’s R&D restructuring enable it to improve its productivity?

Simvastatin (Merck's Zocor)

Simvastatin (Merck’s Zocor)

On December 27th, 2013 the Wall Street Journal published an article by staff reporters Peter Loftus and Jonathan Rockoff about Merck’s new R&D restructuring. Fierce Biotech’s John Carroll also discussed the WSJ article in his own analysis dated December 28th, 2013.

According to these articles, Merck is in the process of cutting its internal R&D operations. This will include selling off dozens of pipeline compounds that have been under development in its labs. Merck also plans to cut its workforce by 20% over the next two years, as it had announced in October 2013. This will include reductions in its internal R&D staff.

At the same time, Merck will create new innovation hubs in Boston, the San Francisco Bay area, London and Shanghai.  The company has identified these geographic areas as having a critical mass of academic and commercial life science R&D. Merck intends to use its hubs as bases to scout for promising research that the company might license or acquire.

The overall plan is to reduce reliance on Merck’s internal R&D operations and to increase reliance on external R&D in academia and in biotech companies.

This is a similar strategy to that being followed by other Big Pharma companies, especially Johnson & Johnson and GlaxoSmithKline. All three of these companies are targeting some of the same geographic areas, especially Boston, California, London, and China.

Why are pharmaceutical companies struggling to develop new drugs?

The unveiling of Merck’s restructuring plans has triggered a wave of articles commenting on the wider implications of the move. David Shaywitz, M.D., Ph.D. (Director, Strategic and Commercial Planning at Theravance in South San Francisco, CA) writes in Forbes (12/29/2013) that pharma companies’ restructuring plans may save neither the companies carrying them out nor the pharmaceutical industry.

The reason that Merck and other pharma companies are carrying out these restructurings is that the companies are struggling to develop new drugs, and their internal labs are not producing them. The hope is that shifting from–as Dr. Shaywitz puts it–research and development to [external] search and development will produce more and better developable drugs. However, it may not do so. Outside partners may not necessarily know more about drug discovery than Merck Research Laboratories does.

The basic question then becomes why pharma companies are struggling to produce new products in the first place. One highly cited possibility is that Big Pharma companies are too bureaucratic, and thus inhibit their own ability to innovate. However, the underlying problem may well be that our understanding of biology–in health and disease–is limited.

The new President of Merck Research Laboratories, Roger M. Perlmutter, M.D., Ph.D. said, as quoted in another Forbes article:

“…if we’re discovering drugs, the problem is that we just don’t know enough. We really understand very little about human physiology. We don’t know how the machine works, so it’s not a surprise that when it’s broken, we don’t know how to fix it. The fact that we ever make a drug that gives favorable effects is a bloody miracle because it’s very difficult to understand what went wrong.”

Dr. Perlmutter then goes on to cite the example of statin drugs such as Merck’s Zocor (simvastatin) and Pfizer’s LIpitor (atorvastatin). Beginning in Merck’s own laboratories, under the company’s legendary R&D leader and CEO Roy Vagelos, statins were designed to lower blood cholesterol levels by inhibiting the enzyme HMG-CoA reductase. However, statins also appear to prevent atherosclerosis by a variety of other mechanisms (e.g., modulating inflammation). Thus their true mechanisms of action are not well understood.

How can companies carry out biology-driven R&D?

Despite the fact that our knowledge of biology is limited, we and others have noted that the most successful drug discovery and development strategy in the last two decades or so has been biology-driven R&D. For example, this is the basis of the entire R&D program of such companies as Novartis and Genentech. How is it possible to conduct reasonably successful biology-driven R&D if our knowledge of human biology is so limited?

We have discussed reasons for the success of biology-driven R&D in our book-length report Approaches to Reducing Phase II Attrition, and in our published article in Genetic Engineering and Biotechnology News “Overcoming Phase II Attrition Problem”.

Briefly, biology-driven drug discovery has often utilized academic research into pathways, disease models, and other biological systems, which have been conducted over a period of years or of decades. Targets and pathways derived from this research are usually relatively well understood and validated, with respect to their physiological functions and their roles in disease.  Examples of drugs derived from such research include most approved biologics (e.g., Genentech’s Herceptin and Biogen Idec/Genentech’s Rituxan), as well as the numerous protein kinase inhibitors for treatment of cancers. It was the successful development of the kinase inhibitor imatinib (Gleevec/Glivec) that led Novartis to adopt its pathway-based strategy in the first place.

A more recent example is the work on discovery and development of monoclonal antibody (MAb)-based immunotherapies for cancer, which we highlighted in our January 3, 2014 blog article on Science’s Breakthrough of the Year. These drugs include the approved CTLA4-targeting agent ipilimumab (Bristol-Myers Squibb’s Yervoy), and several other agents that target the PD-1/PD-L1 checkpoint pathway, including Merck’s own anti-PD-1 agent lambrolizumab.

The development of these agents was made possible by a line of academic research on T cells that was begun in the 1980s by James P Allison, Ph.D. Even after Dr. Allison’s research demonstrated in 1996 that an antibody that targeted CTLA-4 had anti-tumor activity in mice, no pharmaceutical company would agree to work on this system. However, the MAb specialist company Medarex licensed the antibody in 1999. Bristol-Myers Squibb acquired Medarex in 2009, and Yervoy was approved in 2011.

The above examples show that although we do not understand human physiology in health and decease in general, we do understand pieces of biology that are actionable for drug discovery and development. This understanding often comes after decades of effort. One strategy for a scout in a Big Pharma innovation hub might be to look for such actionable pieces of biology, and to contract with the academic lab or biotech company that developed them for licenses or partnerships. However, the case of Yervoy shows that pharmaceutical companies may not recognize these actionable areas, or may be slow to do so.

Moreover, for many diseases of great interest to physicians and patients, academic researchers, and/or companies, we may not have an actionable piece of biology that is backed by decades of research. We may only have interesting (and perhaps breakthrough) research that has been carried out over only a few years. In these cases (and even in cases based on deeper understand based on decades of research), companies will need to develop a set of “fail fast and fail cheaply” strategies. Such strategies usually reside in small biotechs rather than in Big Pharmas. Moreover, these strategies remain a work in progress.


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

Breakthrough of the year 2013–Cancer Immunotherapy

Happy New Year! Source: Roblespepe.

Happy New Year! Source: Roblespepe.

As it does every year, Science published its “Breakthrough of the Year” for 2013 in the 20 December 2013 issue of the journal.

Science chose cancer immunotherapy as its Breakthrough of the Year 2013.

In its 20 December 2013 issue, Science published an editorial by its Editor-in-Chief, Marcia McNutt, Ph.D., entitled “Cancer Immunotherapy”. The same issue has a news article  by staff writer Jennifer Couzin-Frankel, also entitled “Cancer Immunotherapy”.

As usual, the 20 December 2013 issue of Science contains a Breakthrough of the Year 2013 news section, which in addition to the Breakthrough of the Year itself, also contains articles about several interesting runners-up, ranging from genetic microsurgery using CRISPR (clustered regularly interspaced short palindromic repeat) technology to mini-organs to human cloning to vaccine design.

In the Science editorial and news article, the authors focus on the development and initial successes of two types of immunotherapy:

  • Monoclonal antibody (MAb) drugs that target T-cell regulatory molecules, including the approved CTLA4-targeting MAb ipilimumab (Bristol-Myers Squibb’s Yervoy), and the clinical-stage anti-PD-1 agents nivolumab (Bristol-Myers Squibb) and lambrolizumab (Merck).
  • Therapy with genetically engineered autologous T cells, known as chimeric antigen receptor (CAR) therapy, such as that being developed by a collaboration between the University of Pennsylvania and Novartis.

The rationale for Science’s selection of cancer immunotherapy as the breakthrough of the year is that after a decades-long process of basic biological research on T cells, immunotherapy products have emerged and–as of this year–have achieved impressive results in clinical trials. And–as pointed out by Dr. McNutt–immunotherapy would constitute a new, fourth modality for cancer treatment, together with the traditional surgery, radiation, and chemotherapy.

However, as pointed out by Dr. McNutt and Ms. Couzin-Frankel, these are still early days for cancer immunotherapy. Key needs include the discovery of biomarkers that can help predict who can benefit from a particular immunotherapy, development of combination therapies that are more potent than single-agent therapies, and that might help more patients, and means for mitigating adverse effects.

Moreover, it will take some time to determine how durable any remissions are, especially whether anti-PD1 agents give durable long-term survival. Finally, although several MAb-based immunotherapies are either approved (in the case of  ipilimumab) or well along in clinical trials, CAR T-cell therapies and other adoptive immunotherapies remain experimental.

In addition to the special Science “Breakthrough 2013” section, Nature published a Supplement on cancer immunotherapy in its 19/26 December 2013 issue. This further highlights the growing importance of this field.

Cancer immunotherapy on the Biopharmconsortium Blog

Readers of our Biopharmconsortium Blog are no strangers to recent breakthroughs in cancer immunotherapy. In the case of MAb-based immunotherapies, we have published two summary articles, one in 2012 and the other in 2013. These articles noted that cancer immunotherapy was the “star” of the American Society of Clinical Oncology (ASCO) annual meeting in both years.

Our blog also contains articles about CAR therapy, as being developed by the University of Pennsylvania and Novartis and by bluebird bio and Celgene. Moreover, the Biopharmconsortium Blog contains articles on other types of cancer immunotherapies not covered by the Science articles, such as cancer vaccines.

We look forward to further progress in the field of cancer immunotherapy, and to the improved treatments and even cures of cancer patients that may be made possible by these developments.

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.