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Medicago

Fighting the flu with tobacco

Researchers around the world continue their scramble to find new ways to develop anti-flu drugs, vaccines and provide better flu surveillance. Dealing with a foe that has the ability to mutate, evolve, spread and evade immunity, whether it’s common strains of influenza, or more fatal forms of infectious disease, vaccine developers are under constant pressure to ensure there’s enough vaccine available for public consumption should an outbreak occur.

The situation is all the more critical when one considers that the wheels are already in motion for a pandemic to hit. Our governments are preparing for it, many companies have pandemic plans in place just in case, and concerns of how hard the next one will hit or its severity are ever present.

Having spent the better part of 25 years working in vaccine development both in the private sector, and as a consultant in formulating the Canadian pandemic plan used in 2009 during the H1N1 outbreak, Andy Sheldon understands the pressing need for new technologies to fight the flu. Today he heads up Medicago Inc., a Canadian biotech company that may offer new hope in the race to produce vaccines more quickly, more cheaply and with higher yields. Hired in 2003 as president and CEO, and charged with the task of transforming the company from research outfit into a commercially viable vaccine manufacturer, he’s very close to accomplishing his task. And the prospects for future growth continue to excite Sheldon, as does solving some of the world’s most pressing infectious disease dilemmas.

Medicago was founded in 1999 by current chief scientific officer Louis P. Vezina and Francois Arcand, with the company’s initial IP spurred by investment from Agriculture Canada.

“The idea from the start for Medicago was to use plants as a tool to create pharmaceuticals, vaccines and biologics,” says Sheldon.

While the broader focus hasn’t changed, the company has made serious inroads on the vaccine development side beginning with the development of therapeutic proteins for such infectious diseases as H5N1 and seasonal influenza.

“Compared with traditional egg-based and cell production systems, plants are uniquely capable of efficient protein expression at very high yields, and as such we believe we have the ability to produce vaccines quickly and cheaply using plants,” says Sheldon.

The company’s technology is unique in that it relies on the use of tobacco leaves to produce vaccines. The the tobacco plants are an Australian breed called Nicotiana benthamiana.

“We use its leaves as a key part of a process which results in the production of what we call virus-like particles, or VLPs,” explains Sheldon.

Virus-like particles simply put, look like the virus but don’t have any genetic material, and because they look the virus, they have the ability to stimulate immune pathways within a host to combat the virus. Medicago researchers working with Nicotiana benthamiana tobacco plants. Photos courtesy of Medicago

“On the outside, the particles look like the virus, but the particles are actually empty and harmless. Essentially, in the case of humans, they trick the human immune system into mounting a defense,” he says. The steps to producing the VLP’s are far simpler than one would imagine. First the plant’s leaves are soaked in a liquid that contains genetic material from the flu virus, which allows the plant cells to download the genetic sequence from the virus. In turn the plants’ cell machinery kicks in to make virus-like particles. The last step is extracting the virus-like particles from the plant. Medicago’s greenhouse in a suburb of Québec City is full of flats of these plants in various stages of growth. The choice to use this breed of tobacco plant says Sheldon is not accidental. “We use these plants because they have less contaminant and are much cleaner to work with. This offers advantages in terms of purification. One can see that through the process the plants also lend themselves well as a manufacturing platform for proteins. What makes these plants even more unique is that they are able to assemble virus-like particles themselves. It starts at the plasma membrane level of the plant and it buds out. Our job is then of course to breakdown the cellulose tissue which holds it in place.”

As such, the company’s pipeline has three distinct components to it: the vaccines created through this process, its proprietary manufacturing technologies (such as the plant-based Proficia™ technology) and the virus-like particles (VLPs) themselves.

One of the lessons learned from past flu pandemics is that when it comes to producing vaccines, both capacity and speed are important. Again, this is an area that Sheldon believes Medicago has a leg up over its competitors. According to Sheldon, Medicago’s process can deliver a vaccine for testing in less than a month after the identification and reception of genetic sequences from a pandemic strain is made.

“Take the last pandemic for instance, which was swine flu (H1N1). The product was available within six to seven months. During this same outbreak, we did our own test run producing an experimental vaccine with our Australian tobacco plants. In comparison, it took us approximately 19 days to have the first doses of the vaccine ready. Using that as an example we believe we could get our product up and ready to go in just months after we have the sequence, literally shaving two to three months off the time it would normally take to have a vaccine ready for public consumption. All we have to do is simply download it (the viral genetic sequence) from the internet and off we go. And the best part, this can be done with any antigen.”

Put more succinctly, this production time frame has the potential to allow vaccination of a wider population before the first wave of any pandemic strike. It is this ability to rapidly respond to a prospective crisis that has parties all over the world interested in Medicago’s technology.

Count the U.S. Defense Advanced Research Projects Agency, (DARPA) among them. As part of the DARPA “Blue Angel” project, DARPA has awarded a US-$21 million grant to Medicago to see if Medicago’s technology can answer the call by putting Medicago’s technology through a ‘rapid-fire’ test.

“The idea behind this project is to produce ten million doses in one month, and from that be in a position to defend U.S. citizens against bio-threats and we expect that we will be able to attain that goal,” says Sheldon.

To facilitate the project, Medicago established a new subsidiary (Medicago U.S.A.) while opening a new facility in the Research Triangle Park in North Carolina. The facility itself is designed to produce up to 120 million doses of pandemic flu vaccine and 40 million doses of seasonal influenza vaccine annually.

Sheldon says the choice to open the facility in North Carolina came down to a number of factors that went beyond the tailoring of the DARPA deal.

“We definitely had some choices in terms of the location when we signed the deal, but the fit was there in North Carolina because of its great workforce and training programs. There is also the fact that tobacco is one of North Carolina’s top crops and teaming with a high volume of life science and biopharma activity, opening the door to partnerships down the line.”

Once Medicago completes the rapid fire test, Sheldon says the company will validate the facility and use it as the manufacturing centre for its influenza vaccines.

As for the status of its products, Medicago’s pandemic H5N1 VLP vaccine has completed Phase 2 clinical trials while its seasonal flu vaccine is beginning Phase 2. The company also has a rabies vaccine which is in the preclinical stage, but Sheldon expects it to be in Phase 1 by early 2013. The caveat is that there is plenty of cash on hand to take these products forward thanks to the $65 million the company was able to raise in 2011. Thus far, 2012 is looking equally as bright.

“Not only have we continued to advance our pipeline, but the company has also made significant strides towards expanding its product candidate pipeline,” says Sheldon, adding that the aforementioned rabies vaccine is a new area of focus for the company, and one with great potential for growth.

“Rabies is an interesting infectious disease because frequently there are worldwide shortages. There’s also the fact that most products for rabies are used for post-exposure rather than pre-exposure. So there is an unmet medical need here. Even more important we are aiming to try and have a vaccine that is not only very efficient, but also could decrease the number of doses.”

The company is also involved in a research collaboration with the U.S. Army Medical Research Institute of Infectious Diseases for the development of a VLP vaccine candidate for the prevention of Ebola. And recently, Medicago was successful in forming a strategic alliance with Mitsubishi Tanabe Pharma to develop a vaccine for rotavirus, a condition that is the most common cause of severe diarrhea among infants and young children.

“In both instances we are hoping to offer something that is unique to what’s currently available for treatment. For example, in the case of rotavirus, there are vaccines available, however they are live vaccines and many countries don’t particularly like live vaccines. Live vaccines are products which have been modified, but they are actually going to replicate in the gut. They have DNA and they are capable of replicating, and that’s how they stimulate immunity. They’re usually not very efficient and they don’t appear to have the same efficacy. Our goal is to create an intra-muscular or intra-dermal approach where we can combine this with other products.”

With all this activity surrounding the company it becomes clear that the opportunities for Medicago in this space are huge, and Medicago is well positioned to make the most of them.

“We find ourselves with a technology that is able to produce very strong and broad bodily protective vaccines. There are companies out there working with tobacco plants, but they’re quite a ways behind us. As it becomes evident that there is real potential in using these plants in this field, I think over time you’ll see more activity in this area. But, no one has done much of what we’ve done before, and certainly no one is as advanced as we are in the clinical pathway,” he said. On top of its vaccine products, Medicago is also conducting research and development in the area of biosimilars. “Making biosimilars entails something very similar to our vaccine development process. Basically, we program the plants to secrete a protein, and thus far in our system we have ten different monoclonal antibodies. Thus, the plan in the coming months is to work on biosimilar targets, using our plants to express these molecules.” Again, what Medicago could offer says Sheldon, is the ability to produce products at low cost. For example, enzymes that could be used in breaking down a chemical

“Making biosimilars entails agent or what could be a product for use in bio-defense programs. something very similar to our The company also has two other products that for the time being, it is keeping vaccine development process. under wraps. One product is being devel-

Basically, we program the oped in partnership with a top ten pharma company, while the other is an undisclosed plants to secrete a protein, internal target which Sheldon calls a high and thus far in our system we risk-high reward project. “You can say this is the secret to our suchave ten different monoclonal cess; our partnerships, both technical and antibodies. Thus, the plan in in business; Our partnerships have definitely helped in our financial model, and the coming months is to work I think institutional investors understand on biosimilar targets, using the story we’re trying to tell, it becomes a lot easier to be able to raise money and our plants to express quite frankly we have been very successful in both these areas. We will be generating these molecules.” revenue through these agreements both from up-front payments and milestones, but also from royalties on net sales from all these projects once we get them to market. It’s a very nice model of revenue generation.” In the meantime the accolades for both Sheldon and Medicago continue to mount. Recently, Sheldon was named “CEO of the Year” at the World Vaccine Congress in Washington, D.C. “Being chosen as the CEO of the Year is an acknowledgement I think of the Medicago team, and what we have accomplished as a company.” Yet there is no denying the impact Sheldon himself has had on the company. Under his direction, the company is ready for whatever comes its way. For more Innovator information visit our PrOFILES Web Portal at

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