Tag Archives: lipid nanoparticle (LNP) delivery

Getting erased from the mRNA/COVID-19 story

Nathan Vardi’s August 17, 2021 article for Forbes magazine about Ian MacLachlan and the delivery system for mRNA vaccines tells a type of story I’ve more often seen in history books. It is reminiscent of the Thomas Edison and Nikola Tesla story of electricity. One gets all the glory while the other is largely forgotten.

I’m especially interested as much of this concerns players in the local (Vancouver, British Columbia, Canada) biotechnology scene. Vardi’s August 17, 2021 article sets the scene,

“The whole mRNA platform is not how to build an mRNA molecule; that’s the easy thing,” Bourla [Pfizer CEO Albert Bourla] says. “It is how to make sure the mRNA molecule will go into your cells and give the instructions.” 

Yet the story of how Moderna, BioNTech and Pfizer managed to create that vital delivery system has never been told. It’s a complicated saga involving 15 years of legal battles and accusations of betrayal and deceit. [emphases mine] What is clear is that when humanity needed a way to deliver mRNA to human cells to arrest the pandemic, there was only one reliable method available—and it wasn’t one originated in-house by Pfizer, Moderna, BioNTech or any of the other major vaccine companies. 

A months-long investigation by Forbes reveals that the scientist most responsible for this critical delivery method is a little-known 57-year-old Canadian biochemist named Ian MacLachlan. As chief scientific officer of two small companies, Protiva Biotherapeutics and Tekmira Pharmaceuticals, MacLachlan led the team that developed this crucial technology. Today, though, few people—and none of the big pharmaceutical companies—openly acknowledge his groundbreaking work, and MacLachlan earns nothing from the technology he pioneered. 

I have three stories (on this blog) mentioning Tekmira (all from 2014 or 2015) and none mentioning Protiva nor, for that matter, Ian MacLachlan.

Back to Vardi’s August 17, 2021 article,

Moderna Therapeutics vigorously disputes the idea that its mRNA vaccine uses MacLachlan’s delivery system, and BioNTech, the vaccine maker partnered with Pfizer, talks about it carefully. Legal proceedings are pending, and big money is at stake. 

Moderna, BioNTech and Pfizer are on their way to selling $45 billion worth of vaccines in 2021. They don’t pay a dime to MacLachlan. Other coronavirus vaccine makers, such as Gritstone Oncology, have recently licensed MacLachlan’s Protiva-Tekmira delivery technology for between 5% and 15% of product sales. MacLachlan no longer has a financial stake in the technology, but a similar royalty on the Moderna and Pfizer-BioNTech vaccines could yield as much as $6.75 billion in 2021 alone. …

Vardi provides evidence (Note: A link has been removed from the August 17, 2021 article excerpt,

Despite their denials, scientific papers and regulatory documents filed with the FDA [US Food and Drug Administration] show that both Moderna and Pfizer-BioNTech’s vaccines use a delivery system strikingly similar to what MacLachlan and his team created—a carefully formulated four-lipid component that encapsulates mRNA in a dense particle through a mixing process involving ethanol and a T-connector apparatus. 

For years, Moderna claimed it was using its own proprietary delivery system, but when it came time for the company to test its Covid-19 vaccine in mice, it used the same four kinds of lipids as MacLachlan’s technology, in identical ratios. 

According to Vardi’s LinkedIn profile: “I am a senior editor at Forbes, where I am responsible for the coverage of hedge funds, private equity, and other big investors. I lead investigative reporting efforts and have written 20 cover stories for Forbes Magazine,” he does not appear to have any medical or bioscience expertise (Bachelor of Journalism from Carleton University [Canada] and Masters of International Affairs from Columbia University [US].) Presumably someone he consulted or someone on his team provided the skills necessary for analyzing the scientific papers and documents.

You may recognize this scientist (from the August 17, 2021 article),

Not everyone ignores MacLachlan. “A lot of credit goes to Ian MacLachlan for the LNP [lipid nanoparticle],” says Katalin Karikó, [emphasis mine] the scientist who laid the groundwork for mRNA therapies before joining BioNTech in 2013. But Karikó, now a frontrunner for a Nobel Prize, is angry that MacLachlan didn’t do more to help her use his delivery system to build her own mRNA company years ago. “[MacLachlan] might be a great scientist, but he lacked vision,” she says.

I have more about Karikó and her role in the mRNA vaccine story here in a March 5, 2021 posting.

As for MacLachlan’s start (from the August 17, 2021 article),

… With a Ph.D. in biochemistry, MacLachlan joined Inex in 1996, his first job after completing a postdoctoral fellowship in a gene lab at the University of Michigan. 

Inex was cofounded by its chief scientific officer, Pieter Cullis, now 75, a long-haired physicist who taught at the University of British Columbia. From his perch there Cullis started several biotechs, cultivating an elite community of scientists that made Vancouver a hotbed of lipid chemistry. 

As companies rise and fall with intellectual property being assigned to one company or other, legal brawls ensue. This was the time that Karikó came knocking on the door, from the August 17, 2021 article,

It was in the midst of all this furious legal fighting that Hungarian biochemist Katalin Karikó first showed up at MacLachlan’s door. Karikó was early to grasp that MacLachlan’s delivery system held the key to unlocking the potential of mRNA therapies. As early as 2006, she began sending letters to MacLachlan urging him to encase her groundbreaking chemically altered mRNA in his four-lipid delivery system. Embroiled in litigation, MacLachlan passed on her offer. 

Karikó didn’t give up easily. In 2013, she flew to meet with Tekmira’s executives, offering to relocate to Vancouver and work directly under MacLachlan. Tekmira passed. “Moderna, BioNTech and CureVac all wanted me to work for them, but my number one choice, Tekmira, didn’t,” says Karikó, who took a job at BioNTech in 2013. 

By this time, Moderna CEO Stéphane Bancel [emphasis mine] was also trying to solve the delivery puzzle. Bancel held discussions with Tekmira about collaborating, but talks stalled. At one point, Tekmira indicated it wanted at least $100 million up front, plus royalties, to strike a deal.

Instead, Moderna partnered with Madden [Thomas Madden], who was still working with Cullis at their drug delivery company, Acuitas Therapeutics.  …

I have been wondering why Acuitas Therapeutics hasn’t been getting all that much attention in the hyperbolic discussions about British Columbia’s (or Vancouver’s) thriving biotechnology scene. (I’ll have more about the ‘scene’ in a later posting.) Perhaps all this legal wrangling is not considered helpful when bragging. (I do have a November 12, 2020 post, which features Acuitas, an interview with its president and chief executive office Dr. Thomas Madden, and an explanation of their technology.)

As for Moderna, I have a special interest as the company has announced plans to open a production facility here in Canada and one of Moderna’s founders is Canadian, Derek Rossi. (He too is mentioned in the March 5, 2021 posting, scroll down to the ‘Entrepreneurs rush in’ subhead; he is not an altogether happy camper.)

Rossi has opinions on how we should be doing things here as noted in a June 17, 2021 article by Barbara Shecter for the Financial Post (Moderna founder says Canada needs to build a biotech hub to avoid ‘getting caught with its pants down next time’). Thank you, Mr. Rossi. (I’m more familiar with clusters than hubs [hubs were a popular topic of conversation about 20 years ago but in Canada we seem more interested in clusters; see John Newbigin’s “Hubs, clusters and regions” on britishcouncil.org for a description of the differences].)

As for Moderna’s response to all of the legal wrangling over mRNA delivery systems, from Vardi’s August 17, 2021 article,

Moderna pursued a different strategy. It filed lawsuits with the U.S. Patent and Trademark Office seeking to nullify a series of patents related to MacLachlan’s delivery system, now controlled by Genevant. But in July 2020, as Moderna was pushing its vaccine through clinical trials, an adjudicative body largely upheld the most important patent claims. (Moderna is appealing.)

I highly recommend reading Vardi’s August 17, 2021 article as I have not done justice to all of the ‘ins and outs’ of the story.

You can see how thoroughly MacLachlan has been erased form the lipid nanoparticle delivery system/COVID-19 vaccine story in this May 24 ,2021 posting (Lipid nanoparticles: The underrated invention behind the vaccine revolution) by Nada Salem at the Science Borealis blog. It is largely a description of the technology and in the last two paragraphs a history of its development with no mention of MacLachlan or any of his companies.

One last thought, I wonder how Vardi found out about MacLachlan. Could someone have brought the story to his attention and who might that have been?

A newish Tekmira results from a merger with OnCore Biopharma

A Jan. 12, 2015 news item on Azonano announces a new business entity, a combined Tekmira Pharmaceuticals (located in North Vancouver, Canada) and OnCore Biopharma (located in Pennsylvania, US),

Tekmira Pharmaceuticals Corporation, a leading developer of RNA interference (RNAi) therapeutics, and OnCore Biopharma, Inc., a biopharmaceutical company dedicated to discovering, developing and commercializing an all-oral cure for patients suffering from chronic hepatitis B virus (HBV) infection, announced today that they have agreed to merge to create a new leading global HBV company focused on developing a curative regimen for hepatitis B patients by combining multiple therapeutic approaches.

A Jan. 11, 2015 Tekmira news release, which originated the news item, provides details including how this merger will affect the work on the Tekmira ebola treatment,

This transaction is expected to bring together the companies’ broad expertise in antiviral drug development, Tekmira’s Phase 1-ready HBV RNAi therapeutic and OnCore’s multiple HBV programs, to build a robust portfolio of compounds aimed at eradicating HBV. The combined company’s most advanced products are expected to be TKM-HBV, an RNAi therapeutic designed to eliminate HBV surface antigen (HBsAg) expression, a key component of host immune suppression, which is on track to begin human clinical trials in the first quarter of 2015; and OCB-030, a second-generation cyclophilin inhibitor focused on the suppression of viral replication, as well as stimulation and reactivation of the body’s immune response, which is anticipated to enter human clinical trials in the second half of 2015. The combined company anticipates progressing additional programs toward the clinic to achieve the goal of expeditiously evaluating combination regimens.

The combined pipeline is expected to target the three pillars necessary to develop a curative regimen for HBV, including assets focused on suppressing HBV replication, reactivating and stimulating the host immune response directed at HBV and eliminating covalently closed circular DNA (cccDNA). The parties believe that, together, these three pillars are the foundation for achieving a curative regimen.

Dr. Mark J. Murray, Chief Executive Officer of Tekmira, said, “We believe that the merger between Tekmira and OnCore has the potential to transform the HBV treatment landscape by bringing together the technologies and science needed to eradicate the virus and develop a cure for this debilitating and deadly disease. Our new company has the potential to advance multiple, highly active, complementary agents into the clinic in rapid succession, and create an HBV therapeutics powerhouse, thereby potentially offering significant benefits to the global medical community working to improve the lives of HBV patients. Importantly, we also believe this transaction has the potential to create significant value for our shareholders.”

Patrick Higgins, Chief Executive Officer of OnCore, said, “Tekmira and OnCore share a vision that effective combination regimens will ultimately cure HBV, a goal now being realized for hepatitis C virus. This merger is expected to bring together the promise of TKM-HBV with our existing HBV portfolio and accelerate our timeline for combination clinical trials. It is expected to deliver both near-term catalysts and long-term value creation. We believe that the ability to rapidly and sequentially combine novel HBV therapeutics is extremely valuable. We intend to utilize our collective expertise in liver disease and a focused development program, as we did at Pharmasset, to expeditiously and efficiently meet our shared goals.”

An Industry-Leading, Multi-Functional HBV Portfolio

Through the combined portfolio, OnCore and Tekmira intend to advance a robust pipeline of assets that uniquely targets the three pillars for delivering a curative regimen for HBV, including suppressing HBV replication, reactivating and stimulating the host immune response directed at HBV and eliminating cccDNA, the stable source of HBV viral genomic material. Post-closing, the combined company’s HBV portfolio is expected to include  product assets, which can be viewed in a chart by clicking on the following  link: http://media.globenewswire.com/cache/14025/file/31117.pdf

“We intend to take a focused, iterative approach to identifying the most effective combination regimens, while applying what we learn at each stage to optimize future compounds and combinations,” said Dr. Michael Sofia, the combined company’s Chief Scientific Officer and an inventor of sofosbuvir (Sovaldi) for the treatment of hepatitis C. “We believe that the ability to combine multiple unique programs housed in the same company is a significant competitive advantage, and should provide considerable efficiency in terms of speed and ease of decision-making. Combining the OnCore and Tekmira HBV portfolios underpins our vision to accelerate the delivery of a curative HBV regimen.”

Non-HBV Programs Continuing to Move Forward

Tekmira is a global leader in the RNAi field, and has created a diverse pipeline of products in development to treat serious human diseases, such as cancer and viral infections, including Ebola. The company has also licensed its leading lipid nanoparticle (LNP) delivery technology to partners around the world.

The management teams and Boards of Directors of Tekmira and OnCore believe that there is significant value in Tekmira’s non-HBV assets and collaborations. TKM-PLK1 is currently in Phase 2 in multiple indications and TKM-Ebola is expected to enter Phase 2 in West Africa in early 2015. Tekmira also maintains an active RNAi research and development effort. The combined management team and Board of Directors plans to continue to move forward with these programs with the goal of maximizing their value.

The news release goes on to describe the deal,

Under the terms of the agreement, the transaction will be carried out by way of a merger pursuant to which OnCore will merge with a wholly-owned subsidiary of Tekmira and thereby become a wholly-owned subsidiary of Tekmira. Upon closing of the transaction the stockholders of OnCore will hold approximately fifty percent (50%) of the total number of outstanding shares of capital stock of Tekmira, calculated on a fully-diluted and as-converted basis using the treasury stock method. The terms and conditions of the transaction are more fully set forth in the Merger Agreement. The implied market value of the combined company, based on the closing price of Tekmira common shares on the NASDAQ Global Market on January 9, 2015, is approximately USD$750 million.

The merger is subject to approval of a majority of the shareholders of Tekmira present, in person or by proxy, at a special meeting of Tekmira shareholders. Completion of the transaction is also subject to customary closing conditions, including regulatory approvals.  The transaction is expected to close in the first half of 2015, shortly after completion of the Securities and Exchange Commission (SEC) review process and receipt of Tekmira shareholder approval. The Tekmira Board of Directors unanimously approved and recommends that Tekmira shareholders vote FOR the proposed transaction at a special meeting of shareholders.

Details regarding these and other terms of the transaction are set out in the Merger Agreement, which will be filed by Tekmira on the SEC website at www.sec.gov and on the Canadian securities administrator’s website at www.sedar.com.

The combined company plans to retain top executives and board members from Tekmira and OnCore. The new company’s management team will include Mark J. Murray, PhD, Chief Executive Officer; Patrick T. Higgins, President and Chief Operating Officer; Bruce Cousins, Chief Financial Officer; Michael J. Sofia, PhD, Chief Scientific Officer; Mark Kowalski, MD, PhD, Chief Medical Officer; Bryce Roberts, Chief Legal Officer; Michael J. McElhaugh, Chief Business Officer; and Michael J. Abrams, PhD, Chief Discovery Officer. William T. Symonds, PharmD, who led the clinical development of sofosbuvir for the treatment of HCV infection at Pharmasset and later Gilead Sciences, Inc., will be Chief Development Officer and lead the clinical development of the portfolio.

Vivek Ramaswamy will serve as Chairman of the combined company; Dr. Daniel Kisner MD will serve as its Vice-Chairman. The combined company will be headquartered in Vancouver, BC.

I don’t understand how a company, OnCore, which is becoming a subsidiary qualifies as an equal partner in a merger but I gather this is business speak. In any event, the truly curious can find the webcast for a conference call about the deal held on Jan. 12, 2015 at 5 am PT (8 am ET)  along with an accompanying presentation here. The webcast will be available only from January 12, 2015 at 9:00 am PT  / 12 noon ET to January 17, 2015 at 9:00 am PT  / 12 noon ET and, for access, you must register on the site.

I have written previously about Tekmira, in a Nov. 19, 2014 post regarding another of its business deals and in a Sept. 23, 2014 post about its ebola treatment.