On the Horizon: HFA Part 1

Last week the bleeding disorders community met in Cleveland, Ohio at Hemophilia Federation of America‘s annual meeting. It was a fabulous time to meet with friends and colleagues, and to learn about new treatments in inhibitors, new drugs in the pipeline and about psychosocial issues. One of the best attended sessions was the one on gene therapy. Entitled “On the Horizon,” the session was a 90-minute review of new products coming our way, and an overview of gene therapy, how it works and who is working on it.
Dr. Sanjay Ahuja, medical director of Rainbow Children’s Hospital, first spoke about “New and Emerging Therapies.” Expression Therapeutics is working on “ET3i,” a recombinant
factor VIII (rFVIII), that should give a higher yield, with the focus on lower cost per unit.
 

Another interesting therapy is called “transgenic.” Pharming Group has found a way to derive transgenic rFVIII from the milk of rabbits. Ahuja explained that scientists have learned how to take a human gene that makes factor VIII, put in rabbits, and have factor expressed through their milk. This is called “lacto-recombinant factor.”

This generated laughs from the audience, and one man gestured like he was milking a cow. And while Ahuja joked that we could get our kids to drink more milk finally, the actual drug would not be in milk to drink, but commercially available as an infusion. It would be cheaper to produce, with a high yield, making factor much more affordable.

 
“New things and better things coming,” Ahuja said.
 
Many people in the audience already knew about the innovative therapy called emicizumab (commercial name: Hemlibra), a bispecific monoclonal antibody that mimics factor VIII by bringing together activated FIX and FX together, replacing the function of FVIIIa. It’s not a factor product! There was a brief discussion about the deaths associated with its use [see our upcoming article in PEN for a detailed discussion on these]. Bioverativ and Shire are also working on bispecific monoclonal antibody and Shire’s is actually a bi/trispecific. These drugs are called “FVIII-Mimetic.”
 
Another innovation for FIX is from Salk Institute/Arcturus Therapeutics, currently in pre-clinical studies. It’s not gene therapy, though it involves taking RNA to the liver to
make factor.
 
On the horizon for inhibitors are products in the FVII market. HEMA Biologics/LFB, are working on an activated FVII.  rEVO Biologics/LFB are working on FVIIa in transgenic rabbits.
 
Even a long acting, subcutaneous FVIIa is being made by Catalyst Biosciences and OPKP Health.
 
Perhaps the biggest surprise of all is rFVIII being made in lettuce at the University of Pennsylvania, and this you do eat!
 
Dr. Stacey Croteau, medical director Boston Children’s Hospital, and Associate Director of the Boston Hemophilia Center next spoke about gene therapy. She gave a brilliant overview, too detailed for here, but if you look at the slides, you’ll get a sense of just how much activity is underway. And all through the four-day conference, I kept hearing chapter leaders talking about not “if” gene therapy occurs, but “when.” More and more, it is becoming a reality.
 
Dr. Croteau first explained that there are three basic types of gene therapy:
1)   Direct therapy (injection into the patient)
2) Cell based (in which you take cells out, alter the genes, then reintroduce the altered cells to the individual, called ex vivo)
3)   gene editing (going directly into a defective gene to make it work)
 
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There was a good discussion of how adeno-associated viruses (AAV) are mostly used as the vehicles (vectors) to introduce the altered genes into the patient. Why a virus? They are good at replicating—viruses need to quickly replicate to infect the host and survive. But Dr. Croteau stressed that the AAV8 is stripped down and rendered harmless, so just the FIX gene is left. It’s then introduced back into the patient and goes to the liver (AAV vectors love the liver!), embeds into hepatocytes (liver cells), degrades and becomes part of that cell and starts to express normal coagulation factors into the bloodstream.
 
Dr. Croteau explained how difficult gene therapy is. You must get the gene delivered to the right cell type in sufficient quantities; then it must switch the gene on, all the time avoiding body’s natural immune response.
 
In 2011 there was the first successful AAV gene therapy for hemophilia B. With high doses, the patients in the clinical study had their factor levels go from severe to moderate and even to the mild range.
 
Not all gene therapy research is using AAV; there are all types of AAV vector subtypes. Looking at the slides, why so many? Not everyone will be eligible to use a particular vector. Just like with factor, one gene therapy won’t fit all. Dr. Croteau concluded that it’s good we have several options for gene therapy, and many look very promising!
 
To learn more about gene therapy trials, you can look at Clinicaltrials.gov
 
And very honorably, the speakers reminded us that those patients who have volunteered and are volunteering for new therapies and gene therapy make it possible for the rest of us to enjoy a higher quality of life. Indeed, they are our heroes.
 
This was a great session to attend; thanks to Drs. Ahuja and Croteau for their presentations! Please read HemaBlog next Sunday when I’ll give an overview of the entire HFA meeting… which was fantastic!
 

Got Rabbits? Their Milk May Treat Inhibitors Someday

PEN has printed in the past articles about coming products, like long lasting and human-cell line products. We’ve also mentioned transgenic animals—which express proteins in their milk that can be used for human treatment of certain disorders. Hemophilia is one of the therapies being researched to create products from transgenic animals. 

Charlton [Massachusetts] farm to raise rabbits for medicine

By Lisa Eckelbecker TELEGRAM & GAZETTE STAFF

A French biotechnology company that turns milk from genetically engineered goats into medicine plans to expand operations at its farm in Charlton by raising rabbits that produce a blood-clotting agent for patients with hemophilia.
LFB SA and its Framingham-based subsidiary rEVO Biologics plan to build a colony of 1,000 to 1,200 rabbits making a protein called Factor VIIa at the farm, said Dr. William Gavin, a veterinarian and senior vice president of operations for rEVO.

“We’re going to have the first shovel in the ground in August,” Dr. Gavin said. “About one year later we will be producing milk here from the rabbits that produce the Factor VII in their mammary glands.”

The plan represents the first potential product expansion at rEVO, previously known as GTC Biotherapeutics, since it launched a clot-busting drug called ATryn in 2009. ATryn was the world’s first drug made in the milk of genetically altered animals.

LFB has been producing limited amounts of Factor VIIa in the milk of rabbits in France while also testing the protein in humans. The company said Monday it expects to launch the third and final phase of human studies this year.

If approved, LFB would market its Factor VIIa product as a treatment for hemophilia A and B patients who have developed inhibitors, or antibodies, to other clotting proteins known as Factor VIII or Factor IX.

The global market for blood disorders, including hemophilia, is estimated to reach nearly $64.7 billion by 2017, according to analyst Usha Nagavarapu in a market research report published last year by BCC Research of Wellesley.

NovoSeven, a Factor VIIa product sold by Novo Nordisk of Denmark, posted worldwide sales of 8.9 billion kroners in 2012, or about $1.6 billion in current dollars.

Founded in 1993 as part of Genzyme Corp., rEVO has offices and laboratories in Framingham. The company developed transgenic animals as an alternative to traditional biologics manufacturing.

Transgenic animal production generally starts in a laboratory, where scientists inject human genes into an early animal embryo. The embryo then gets implanted in the womb of a surrogate mother. If the procedure is successful, the animal born will carry code for a human protein in its genes. Then the animal can be bred normally to produce offspring with the human code.

That is how rEVO built its herd of goats on its 383-acre Charlton farm. Transgenic females in the herd produce milk carrying antithrombin III, a protein involved in blood clotting. The company processes the milk to a sterile powder form of antithrombin III for sale.

Dr. Gavin said rEVO plans to bring transgenic New Zealand White rabbits from France to build a new Charlton colony. The company chose rabbits rather than goats to produce Factor VIIa because rabbits can produce the key protein with certain sugars needed for the best therapeutic results.

Rabbits can also produce 200 milliliters of milk per day, or nearly 7 ounces, and they lactate for about three weeks.

Contact Lisa Eckelbecker at lisa.eckelbecker@telegram.com. Follow her on Twitter @LisaEckelbecker. 

So I just saw this in the newswires… and go here to read about my visit to this farm a few years ago, and to see pictures of the goats mentioned in the articles. 
http://blog.kelleycom.com/search/label/GTC%20Biotherapeutics
You can also learn more here: http://www.transtechsociety.org/livestock.php

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Factor Through Goats?

A persistent question we are always asked is “What ever happened to gene therapy?” We used to write extensively about this subject when gene therapy was hot, but since the deaths of two young people in gene therapy trials unrelated to hemophilia, all gene therapy seems to have taken a slow and extremely cautious route. There instead seems to be great interest in creating new and less expensive ways to manufacture factor. We recently heard of a new biotech company in California, founded by a parent of a child with hemophilia, that is developing all therapies, which hints that these products one day will be lower in cost.

And the newswires announced this last week: GTC Biotherapeutics, a Massachusetts-based biotech company, held a webcast this morning from Monaco; the webcast will be available tomorrow through the company’s website. This company “develops, produces, and commercializes therapeutic proteins through transgenic animal technology.” This means literally milking animals for the desired protein that is developed through gene therapy and then expressed through the animal’s milk.

Like many, I feel a bit skeptical but according to GTC, in August 2006 its recombinant form of human antithrombin was approved by the European Commission for use in patients with hereditary antithrombin deficiency undergoing surgical procedures. This was the first approval anywhere in the world of a therapeutic protein produced from a transgenic animal. GTC has developed goats that have the human antithrombin gene linked to a milk-protein promoting gene so that they express this protein in their milk.

In 2006, GTC was granted a patent in the United States through 2021 for the production of any therapeutic protein in the milk of any transgenic mammal. And GTC has established a strategic collaboration with LFB Biotechnologies of France to jointly develop recombinant human factor VIIa as a potential treatment for hemophilia inhibitor hemophilia patients. This would be a direct competitor to NovoSeven, apparently. Although the article doesn’t directly state this, it implies that this recombinant FVIIa would be expressed by animals?

It bears watching, and we hope to bring more infromation about this through PEN and through HemaBlog. Watch the webcast yourself tomorrow at the GTC web site, www.gtc-bio.com.

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