Remember when naked DNA was all the rage?

The forgotten history of Vical

[note: As always, I’ve included a graphical timeline for reference at the end of this article]

In the autumn of 2019, as the world turned normally for all of us blissfully unaware humans, something rather strange occurred - a gene therapy company that had previously produced the one and only SARS-CoV vaccine ever tested in human trials in the US quietly disappeared from existence.

There is no Wikipedia page for this company. I’m not sure if there ever was one. Yet, this company once attracted both the Rockefeller and Rothschild venture capital arms. It also attracted heavy interest from the Bill and Melinda Gates Foundation.

All of that attention just to vanish like a vapor? Seems incredibly suspicious to me.

This is the story of a company called Vical. Strange name, you say? Yes, I agree. The founder, Tim Wollaeger, seemed a bit fuzzy when asked how the name came about¹:

I liked Karl [Hostetler] and thought he was creative, and he educated me on osteoporosis and the big markets for calcitonin in Europe and Japan, but it wasn’t doing much in the US because, basically, the body cleared it, and I thought, ‘Gee, that makes sense,’ and so we started Vical. And we included his lab partner because of some ethical challenges from the university, and this guy, Doug Richman, was working on viruses, so Vical was viruses and calcitonin, Vical — or it was Viva California, I asked Karl the other day which it was and he couldn’t remember, but we probably came up with the name for both reasons.

That’s a cute story, and it may be the truth as far as I can tell about the origin of the company name, but it certainly does not disclose any details about the real reason that Vical was founded.

In the beginning there was…Liposomal AZT

Vical was incorporated in San Diego, CA in 1987² by the aforementioned Tim Wollaeger, who was a former vice-president of Baxter International where he was responsible for the company’s operations in Mexico, and Howard (Ted) Greene, who was also a former Baxter executive and former president of a biotech called Hybritech. Tim and Ted started a venture capital firm called Biovest Partners just prior to founding Vical.

Within a year of its incorporation, Vical had managed to draw the attention of several venture capital firms including Mogenthaler, The Hillman Company, Sutter Hill Ventures, Sequoia Capital and Security Pacific Capital. At that time, Vical was described as a company focusing on the “development of drugs for the treatment of AIDS, herpes and other viral diseases”³.

Another year later and Vical would land a large research contract with Burroughs-Wellcome to develop liposomal AZT for AIDS treatment. That phrase- liposomal AZT-actually sends shivers down my spine. As if straight AZT wasn’t bad enough, someone thought it must have been a good idea to drive it as far into the cell as possible to do the most damage (to HIV only, of course).

So, this is where Phil Felgner, an expert in liposomes and soon-to-be colleague of Robert W Malone, enters the picture. Felgner was hired by Vical in 1988 to work on the Burroughs-Wellcome project to develop liposomal AZT. He actually admitted this in an interview with Mark Jones for the San Diego Technology Archive in 1997⁴:

Jones: Did those guys recruit you to Vical because of your expertise in liposomes?

Felgner: Yeah, they felt that I could do that project, to encapsulate the AZT in liposomes and develop a product, so there was a technical challenge, to develop a pretty complicated delivery system, and a pretty complicated formulation. They felt that I had the know-how to carry that out. And I did. We did exactly what we were intending to do for Burroughs-Wellcome, under contract, that whole thing proceeded for three or four years.

During the same interview, Felgner also revealed the real reason for Vical in response to a question about when he had first attempted to deliver DNA to cells using liposomes while working at Syntex:

Jones: What year was this?

Felgner: That was around 1984. So we patented all this at Syntex, and then published on it. And these guys got wind of that result, Karl Hostetler, Dennis Carson, and Doug Richman, and they had their own ideas about what they wanted to do for Vical, to do this nucleotide anti-viral project with liposomes.

There you have it. Three years before Vical came into existence, a course was already being plotted to deliver nucleotide therapeutics to cells using liposomes.

Say it ain’t so Dr. Malone

According to Felgner, the liposomal AZT project lasted from 1989 to about 1992. The question that naturally arises here is what was the extent, if any, of Dr. Robert W. Malone’s involvement with this project?

Dr. Malone’s resume states that he was a research scientist at Vical for only one year in 1989. Yet, somehow during this time he was able to setup Vical’s molecular biology laboratory and discover naked DNA gene therapy. That just seems incredibly unrealistic to me. I think a more realistic scenario would be that the gap in Dr. Malone’s resume between 1990 and 1991 was possibly filled by more work at Vical. If that is the case, then he was at Vical for the entire duration of the liposomal AZT project and it is difficult to see how he would not have been involved in some way.

Tangential Weirdness

In 1989, both Felgner and Malone were simultaneously working for both Vical and the Salk Institute. The pair published a paper that year listing the Salk Institute as their affiliation which described their work on liposome-mediated RNA transfection⁵.

I was just a bit curious as to what other activities/events were occurring at the Salk Institute around this time period. One rather strange thing I found was that the President of the Salk Institute, Dr. Frederic de Hoffmann, was diagnosed with AIDS in late 1988. Apparently, he contracted HIV from a blood transfusion he received during a surgery in 1984⁶. Within a year he would perish from his infection. How absurdly ironic is it that the President of the Salk Institute, an organization that focused heavily on AIDS treatment, would be diagnosed with AIDS?

This is the only picture I could find of Dr. Hoffmann. Very poor quality. Source: The Los Angeles Times, 06 Oct 1989.

The story gets even stranger. It turns out that Dr. Hoffmann was a nuclear physicist who participated in the Manhattan Project at Los Alamos, NM. He also assisted Edward Teller in the development of the hydrogen bomb in 1951⁷. After that, he went on to work for General Dynamics Corp. in 1955 and convinced the company's president to start General Atomics. He served as the president of that company and was also an executive of Gulf Oil Corp. until 1970, when he very strangely decided to completely change careers by accepting the leadership role at Salk.

One more thing. There is at least one other intersection of the Dr. Hoffmann story with Vical. According to Vical founder Tim Wollaeger, Vical started out in a building that was leased to it by General Atomics. Vical rented the building shortly after Dr. Hoffmann had been diagnosed with AIDS and stepped down as president of the Salk Institute.

I mean, is that not a totally bizarre story?

Naked DNA all the way

While Vical was initially focused on the liposomal AZT project, it was at the same time undergoing a bit of an identity crisis. Felgner said that the company leadership was torn between focusing on liposomal AZT or naked DNA transfection. As the funding from Wellcome-Burroughs began to dry up the shift to naked DNA became more enticing to Vical.

In 1990, Vical researchers (including Felgner and Malone) published a breakthrough study on naked DNA transfection in mice in the journal Science⁸. Vical received a great deal of public exposure from this study, and shortly thereafter, Merck initiated a huge collaboration with Vical to develop naked DNA vaccines.

It wasn’t very long before the heavy-duty venture capitalists moved in. In early 1992, Patrick Latterell joined the board of directors of Vical. At that time he was a General Partner with Venrock Associates, a Rockefeller investment firm. He had also been a General Partner at Rothschild Ventures from 1985 to 1989. Prior to that, Latterell was a corporate development manager at Syntex from 1983 to 1985.

Prior to going public in 1993, Venrock Associates (via Patrick Latterell) required the sale of all of Vical’s intellectual property related to liposomal AZT to a company called Vestar, Inc. Vestar then went on to merge with NeXagen out of Boulder, CO to form Nexstar Pharmaceuticals, Inc. As far as I can tell, Nexstar only ever brought two drugs to market - AmBisome and DaunoXome, which were both liposomal drugs targeting antifungal and anticancer treatments. Nexstar was bought by Gilead Sciences in 1999.

Another event that took place before going public was the hiring of Alain Schreiber as CEO. He had previously served in various leadership positions at Rhone-Poulenc Rorer and Syntex. He was also an adviser for foreign trade of the Belgian Foreign Trade Counsel in the US and a fellow at the Weizmann Institute in Israel.

Let the good times roll

Between 1993 and about 2012, Vical engaged in a wide variety of research and licensing activities in an effort to monetize its naked DNA technology. The company had three main focus areas for its product pipeline: cancer vaccines and therapeutics, therapeutic proteins and infectious disease vaccines. In order to achieve progress in these areas, Vical relied on several key partnerships:

• DoD/DARPA:

  • Vical entered a CRADA with the US Navy in 1993 to develop a malaria vaccine

  • DARPA provided a grant of $500K to Vical in 2005 for feasibility studies on rapid manufacturing of large quantities of naked DNA vaccines

  • The US Navy contracted Vical to manufacture a naked DNA vaccine for dengue fever in 2008 and H1N1 in 2009

• NIH/NIAID:

  • NIH contracted Vical to manufacture naked DNA vaccines for clinical trials in 2001

  • NIAID provided a grant in 2002 to develop an anthrax vaccine

  • In 2004, Vical signed an agreement with NIH to manufacture HIV, Ebola, West Nile and SARS-CoV vaccines

  • NIAID provided a $3M grant to Vical in 2005 to develop a pandemic influenza vaccine

  • NIAID provided a $6M grant to Vical in 2007 for rapid manufacturing of naked DNA vaccines

  • NIAID contracted Vical to manufacture an AIDS vaccine for IPPOX foundation trials

• Bill and Melinda Gates Foundation:

  • Vical received funding in 2010 to develop a naked DNA measles vaccine with VaxFectin adjuvant and a naked DNA AIDS vaccine

• Commercial:

  • A long-term collaboration with Merck began in 1991 and continued through 2012. Merck was interested in developing naked DNA for all sorts of diseases including influenza, HIV, Hepatitis B/C and cancer. Merck also licensed naked DNA for use in tissue revascularization. It’s not clear to me why Merck did not just buyout Vical. It certainly had a heavy interest in the technology, which is evidenced by the number of senior management and board members at Vical who had previously held high-level positions at Merck.

  • Pasteur Merieux Connaught licensed naked DNA technology for infectious disease vaccines in 1995

  • Rhone Merieux and Vical formed a corporate alliance in 1995 to develop naked DNA vaccines for use in domesticated animals

  • Rhone-Poulenc Rorer licensed naked DNA for the delivery of neurologically active proteins in 1997

  • Pfizer licensed naked DNA for delivery of therapeutic proteins in animals in 1999

  • Sanofi licensed naked DNA for delivery of fibroblast growth factor 1 (FGF-1) in 1999

  • Vascular Genetics, Inc. licensed naked DNA for delivery vascular endothelial growth factor-2 (VEGF-2) in 2000. Human trials were controversial at the time as several patients died following treatment⁹.

  • Aqua Health Ltd in Canada licensed naked DNA for infectious haematopoetic necrosis virus in wild and farm-raised fish. This vaccine received approval from Canadian regulators. The extent of its use is uncertain.

  • AnGes licensed naked DNA for cardiovascular tissue revascularization via delivery of hepatocyte growth factor (HGF) in 2005. Vical also collaborated with AnGes in 2014 to develop a naked DNA vaccine for Ebola.

  • Astellas licensed naked DNA for development of a cytomegalovirus in 2011

  • Bristol-Myers Squibb licensed naked DNA and VaxFectin adjuvant for the production of therapeutic antibodies in 2012

Looking over the above list, one might be inclined to think that there must have been at least a few naked DNA products for humans that made it to market. Nope. Although there were several Phase I-III trials in humans, no naked DNA vaccine or therapeutic ever received approval.

The only products that did make it to market were Apex-IHN which was a naked DNA vaccine for salmon and ONCEPT which was a melanoma treatment for dogs.

The SARS-CoV connection

One interesting fact about Vical is that it is the only company to ever have been contracted by the NIH to produce a vaccine for SARS-CoV for use in human trials. The Phase I trial, announced in 2004, used a naked DNA plasmid encoding the spike protein of SARS-CoV. The vaccine was administered to study participants using the Bioinjector 2000 manufactured by Bio-Ject. This needle-free device was designed to deliver therapeutic agents subcutaneously or intramuscularly.

After the Phase I trial using Vical’s naked DNA was completed, there were a couple of other Phase I applications from Baylor University and the University of Iowa. Both of these studies were designed to evaluate more traditional vaccine technologies for SARS-CoV. Neither of them progressed past the recruitment phase before being withdrawn.

So, it would appear that NIH was only interested in testing naked DNA (gene therapy) vaccines for SARS-CoV.

Sliding into oblivion

It’s a bit difficult to keep a business running when you can’t get any of your products to market. By 2013, Vical’s pipeline had pretty much dried up completely due to the reluctance of regulators to approve naked DNA therapeutics/vaccines for use in humans. Remember, this was back in the good old days when we still had some semblance of a functioning regulatory apparatus. Well, it was good for most of humanity, but bad for Vical.

After 2013, the company was really just phoning it in as far as I can tell with nothing much at all happening on the product development front. The final capitulation came in 2019 when Vical announced a reverse merger with Brickell Biotech.

As a result of the merger, Vical surrendered its name and all of intellectual property. Brickell apparently buried all of the IP in the backyard because there was really no mention of naked DNA in the newly formed company, which instead focused on developing an antifungal drug. There was one exception, however. In 2020, Brickell announced a collaboration agreement with AnGes to develop a naked DNA vaccine for covid. This collaboration, of course, went nowhere and was quickly ended once the mRNA vaccines began to sweep the world.

In 2022, Brickell Biotech changed its name to Fresh Tracks Therapeutics, further obscuring the “old tracks” left behind by Vical. Presumably, Fresh Tracks still holds whatever IP still remains from Vical.

Summary

My impression is that the main purpose of Vical was never to make a profit, but rather to fully explore the possibilities of gene therapy using naked DNA transfection. I believe that the weight of Rothschild/Rockefeller on the board of directors ensured that the company was not bought out and was therefore able to license its technology to an array of pharmaceutical companies who could explore different aspects of the technology.

It seems apparent to me that an attempt has been made to bury this company in the past. Why?

1. Interview with Tim Wollaeger, 1997.

2. I have been noticing a strange pattern of biotech businesses that were incorporated in Delaware not showing up in the Secretary of State database. This is also the case for Vical. The California incorporation filing shows a copy of the Delaware incorporation certificate, but there is no entry for Vical in the Delaware database.

3. The Los Angeles Times, 29 Sep 1988.

4. Interview with Phil Felgner, 1997.

5. Malone RW, Felgner PL, Verma IM. Cationic liposome-mediated RNA transfection. Proc Natl Acad Sci U S A. 1989 Aug;86(16):6077-81.

6. Scrantonian Tribune, 18 Nov 1988, Page 25.

7. Chicago Tribune, 08 Oct 1989, Page 48.

8. Wolff JA, Malone RW, Williams P, Chong W, Acsadi G, Jani A, Felgner PL. Direct gene transfer into mouse muscle in vivo. Science. 1990 Mar 23;247(4949 Pt 1):1465-8.

9. The Boston Globe, 21 May 2000, Page 456.