On August 10, 2018, Alnylam Pharmaceuticals (Cambridge, MA) announced the first-ever FDA approval of an RNAi (RNA interference) drug. The drug is Alnylam’s patisiran, which is indicated for the treatment of polyneuropathy due to transthyretin-mediated amyloidosis (ATTR). ATTR is a rare inherited, debilitating, and often fatal disease caused by mutations in the transthyretin (TTR) gene. Patisiran is trade-named “Onpattro”. The FDA approved patisiran for the treatment of polyneuropathy in adults with hereditary transthyretin-mediated amyloidosis (hATTR) in adults.

On August 30, 2018 Alnylam announced that the European Commission (EC) has granted marketing authorization for patisiran for the treatment of hATTR in adults with stage 1 or stage 2 polyneuropathy.

Shortly after Alnylam’s initial announcement, Nature published a news article in its 16 August 2018 issue, entitled “Gene-silencing technology gets first drug approval after 20-year wait”, by senior reporter Heidi Ledford, Ph.D.

As discussed in the Nature article, patisiran is the first-ever FDA approved drug based on RNA interference (RNAi), a specific gene-silencing technology. Two researchers—Andrew Fire of Stanford University School of Medicine in California and Craig Mello of the University of Massachusetts Medical School in Worcester—shared the Nobel Prize in Physiology or Medicine in 2006 for their 1998 publication of their discovery of RNAi. However, it took 20 years from the original discovery of RNAi until the first RNAi drug was approved by the FDA. The main technological issue that needed to be overcome to turn RNAi into drugs was drug delivery.

Formulation of the RNAi agent patisiran in lipid nanoparticle carriers

We discussed patisiran (then also known as ALN-TTR02) in our January 24, 2014 article on this blog. Patisiran consists of a specific oligonucleotide molecule encapsulated in a lipid nanoparticle (LNP) carrier (formerly known as a SNALP—stable nucleic acid lipid particle). The oligonucleotide is designed to inhibit expression of the gene for TTR via RNA interference. The LNP (see the Figure above) is based on technology developed by Alnylam’s partner Arbutus Biopharma (formerly known as Tekmira). LNP-encapsulated oligonucleotides accumulate in the liver, which is the site of expression, synthesis, and secretion of TTR.

The carrier used in patisiran is a second-generation LNP that contains combinations of synthetic ionizable lipid-like molecules known as lipidoids. This strategy was developed by Alnylam in collaboration with Dr. Robert Langer’s laboratory at MIT. The second-generation LNP renders patisiran much more potent than the first generation version of Alnylam’s anti-TTR product, ALN-TTR01. In a Phase 1 clinical trial (referenced in our January 24, 2014 blog article), 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.

On September 20, 2017 Arbutus announced the success of a Phase 3 clinical trial of Alnylam’s second-generation LNP-encapsulated anti-TTR agent, patisiran.

We included a detailed discussion of the development of second-generation LNP-encapsulated RNAi products, especially ALN-TTR02/patisiran, in Chapter 4 of our book-length report, RNAi Therapeutics: Second-Generation Candidates Build Momentum, published by Cambridge Healthtech Institute’s Insight Pharma Reports in October 2010.

Phase 3 clinical trial of patisiran published in the New England Journal of Medicine

The New England Journal of Medicine (NEJM) published a Phase 3 trial (known as APOLLO) of patisiran in patients with hereditary transthyretin amyloidosis (hATTR) in its July 5, 2018 issue.  According to Alnylam, the FDA approval of patisiran was based on the positive results of this trial. APOLLO was a randomized, double-blind, placebo-controlled, global Phase 3 study, and was the largest-ever study in hereditary ATTR amyloidosis patients with polyneuropathy.

The APOLLO study showed that patisiran treatment improved measures of polyneuropathy, quality of life, activities of daily living, ambulation, nutritional status and autonomic symptoms–as compared to the placebo group, in adult patients with hATTR amyloidosis with polyneuropathy. The most common adverse events in patisiran-treated patients were upper respiratory infections and infusion-related reactions. The risk of infusion-related reactions could be reduced via premedication prior to infusion.

RNAi as a premature technology, and the need to move it up the technology development curve

In our July 13, 2009 article on this blog, I mentioned the presentation that I gave earlier that year at a conference entitled “Executing on the Promise of RNAi” in Cambridge MA. My presentation was entitled, “The Therapeutic RNAi Market – Lessons from the Evolution of the Biologics Market”. In that presentation, I compared the field of monoclonal antibody (mAb) drugs to that of RNAi drugs. Despite the high level of investment in therapeutic RNAi over nearly 20 years, the formation of numerous biotech companies specializing in RNAi drug development, and the strong interest of Big Pharma in the field, there still was not one therapeutic RNAi product on the market until the August 2018 launch of patisiran. At the time of the 2009 conference—and beyond—researchers envisioned significant hurdles to the development of RNAi drugs, especially those involving systemic drug delivery. Many experts therefore believed that therapeutic RNAi was scientifically and/or technologically premature.

As of the past 15-20 years, mAbs have represented the most successful class of biologics. However, the therapeutic MAb field went through a long period of scientific prematurity, from 1975 through the mid-1990s. Several enabling technologies, developed from the mid-1980s to the mid-1990s, were necessary for the explosion of successful MAb drugs, from the mid-1990s to today. Similarly, many companies and academic laboratories have been hard at work developing enabling technologies to move the therapeutic RNAi field up the technology development curve.

As catalogued in our blog, large pharmaceutical companies that had partnered with RNAi specialty biotechs and/or were pursuing their own internal RNAi drug development, dropped our of RNAi—one by one. These included Roche, Pfizer, Merck and Novartis. This was all due to the technological prematurity of the therapeutic RNAi field, especially the issue of drug delivery.

However, as of 2018, the suite of enabling technologies behind the second-generation LNP that has been incorporated into patisiran made the successful development and approval of this drug possible. The development of these technologies and delivery platforms at Alnylam and its partners—including laboratory, preclinical and clinical studies—took place over nearly a decade prior to the approval of patisiran.

As discussed in our book-length report, Alnylam and other RNAi specialty companies have been developing suites of liver-targeting therapeutics. For example, Alnylam is developing liver-targeting RNAi therapeutics for such conditions as acute hepatic porphyrias, hemophilia, and hypercholesterolemia. These clinical-stage RNAi therapeutics utilize Alnylam’s recently-developed liver-targeting Enhanced Stabilization Chemistry (ESC)-N-acetylgalactosamine (GalNAc) delivery platform rather than the RNP delivery vehicle.

However, according to Alnylam cofounder Thomas Tuschl, Ph.D. (Rockefeller University and the Howard Hughes Medical Institute, New York, NY), as quoted in the August 2018 Nature News article, Alnylam and other RNAi specialty companies are also working on RNAi-based therapies that are designed to target organs other than the liver. For example, Quark Pharmaceuticals (Fremont, CA) is testing RNAi therapies that target the kidneys and the eye. Alnylam is developing therapies that target the central nervous system (CNS), and Arrowhead Pharmaceuticals (Pasadena, CA) is developing an inhalable RNAi therapeutic for cystic fibrosis.

Rare-disease drug development and RNAi

Recently, there has been a controversy about development of drugs for rare diseases. This has been played out between an article by Milton Packer MD (Distinguished Scholar in Cardiovascular Science, Baylor University Medical Center) on Medpage Today and one by John LaMattina, Ph.D. (Senior Partner, PureTech Health; former President of R&D, Pfizer) in Forbes.

Rare diseases (as defined by NIH) are diseases that affect fewer than 200,000 individuals. There are an estimated 7,000 rare diseases. Some of the more common of these diseases are well known: e.g., muscular dystrophy, cystic fibrosis and multiple sclerosis. Many forms of cancer can also be considered rare diseases. Although each of these diseases is “rare”, the aggregate number of rare-disease patients in the U.S. is—according to the NIH—25 million. Thus “rare-disease patients” are not rare at all.

Dr. Packer argues that:

• the pharmaceutical industry is obsessed with rare-disease drugs;
• the FDA is less stringent about the types of data that it requires for approval for a new rare-disease drug;
• pharmaceutical companies have found that they can charge exorbitant prices for rare-disease drugs;
• if a company decides to develop a new rare-disease drug, the development costs will be low compared to drugs for more common diseases, the return on investment can be enormous, and the developer will have marketing exclusivity for many years.

Dr. LaMattina counters that the first two of these statements are not true. Moreover, even though rare-disease drugs command a high price, they still may lower the cost of treatment. If a rare disease costs the healthcare system $200,000/patient/year, and a new drug for this disease both ameliorates the disease and reduces other costs for treating these patients, a price of $100,000/patient/year can be a bargain – as well as help the patient. Payers thus often accept the high prices of rare-disease drugs.

With respect to market exclusivity, all drugs—whether for rare diseases or not—get the same length of patent exclusivity. There can also be tremendous competition in rare disease R&D leading to the potential for multiple drugs (and types of drugs) to treat specific rare diseases. This competition can also drive down prices.

An important issue that was not discussed in this exchange is that rare-disease research makes possible development of totally new types of therapies that may eventually be used for more common diseases. The development of patisiran—the first ever approved RNAi therapeutic—for the rare disease ATTR is a prime example. Gene therapy also represents an entirely new suite of technologies that have been first applied to rare diseases. See, for example, the recent approval of Spark’s Luxturna (voretigene neparvovec-rzyl) for the treatment of a rare inherited retinal disease. Several CAR-T (chimeric antigen receptor-T cell) therapies have been recently developed and approved for treatment of several types of rare hematologic cancers. Other CAR-T therapies are being developed for cancers that still do not have good treatment options. Meanwhile, the first clinical trial of a treatment based on the gene-editing technology known as CRISPR-Cas9 for the rare diseases beta thalassemia and sickle cell disease has recently launched.

Thus the rare disease field has been and will continue to be a fertile area for the development and application of novel therapies. Some of these therapies may eventually be applied to more common diseases. In particular, this includes RNAi-based therapies.

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