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!

It’s New! Therapeutic! And Coming Soon!

Dr. Glenn Pierce
With a record-breaking 2,987 in attendance, NHF’s 69th annual meeting in Chicago on August 24-26, was the largest and most varied!
Two of my favorite speakers at NHF Annual Meetings and whose sessions I always seek out, are Glenn Pierce, MD, PhD and Steven Pipe, MD. And they did not disappoint! Although it would take an entire blog to list all of the accomplishments of these two highly respected individuals, suffice to say that they are both very knowledgeable about bleeding disorders in general and about clotting factors, novel treatments and gene therapy in particular. And they both share a relatively rare ability: they are able to explain complex medical topics to consumers in terms that we can understand (okay, mostly understand!)
In Dr. Pipe’s Friday morning session, “The Cure Horizon: Point/Counterpoint”, whom he co-hosted with Dr. Rebecca Kruse-Jarres, Pipe played the part of advocate for gene therapy and his counterpart advocated for “small molecules” (novel, non-factor treatments for preventing bleeds). Later that day Dr. Pierce gave the plenary session on “New Treatments and Gene Therapy.” Although both sessions covered some of the same information, they did so from different perspectives and it was beneficial to attend both.
Dr. Steven Pipe
Here’s a recap of the two talks regarding new therapies on the horizon. On the “small molecule” side there are three different approaches being investigated that can reduce bleeds without the use of factor. One therapy, emicizumab, or better known in the community as ACE910, is likely to be the first to market—and soon. ACE910 is a therapy for hemophilia A ,with or without inhibitors. It is a bi-specific antibody (meaning the antibody can grab two different factors at once) designed to mimic the function of factor VIII by bringing together factors IXa and X to initiate clotting. It is
administered weekly as a subcutaneous injection. Genentech’s ACE910 has been granted priority review by the FDA and their license application may be approved as soon as February 2018. (It was also mentioned that repeated doses of aPCC, a by-passing agent sometimes used by people with inhibitors, in conjunction with ACE910 can result in unwanted clotting.)
A second approach involves blocking the function of a player in the clotting cascade called tissue factor pathway inhibitor (or TFPI) that serves to check the clotting process so it does not runaway out of control. This therapy, called concizumab or anti-TFPI, is also an antibody and also administered subcutaneously. It blocks the function of TFPI and is effective in reducing bleeds in people with hemophilia A, B as well as those with inhibitors. Anti-TFPI has entered phase 2 clinical trials this summer.
The third approach uses genetic material that blocks a cell’s ability to produce antithrombin, which like TFPI, serves as a check on
coagulation. Called fitusiran, this agent interferes with the cell’s RNA involved in the production of antithrombin—in short, it prevents the cell from making antithrombin and restores a “balance” between the two parts of the clotting process: one that makes clots and the other that stops the clotting process. This agent is in phase 2 clinical trials.
All three of these novel hemophilia treatments were referred to as “disruptive therapies.” This is similar to the term “disruptive technologies,” which “refers to any enhanced or completely new technology that replaces and disrupts an existing technology, rendering it obsolete. It is designed to succeed similar technology that is already in use”1. Examples of disruptive technologies include DVRs, which displaced VHS recorders; PCs, which displaced both typewriters and mainframe computers; and laptops, which displaced desktop PCs and might soon find themselves displaced by tablets; and tablets which may be replaced by ever-larger and more powerful smart phones, which themselves have disrupted the telecommunications industry. The emerging small molecule therapies for hemophilia will be more convenient, last longer, be easier to administer and will likely be less expensive than clotting factor concentrates. They will upend the market for factor concentrates, which have been the mainstay treatment for hemophilia in developed countries since the late 1970s. And, of course, gene therapy is on the horizon, which will then disrupt the market for small molecule therapies for hemophilia.
And what about gene therapy? Both speakers mentioned significant advances made by two companies, Spark and BioMarin, which have been successful in converting individuals with severe hemophilia into mild hemophilia, with Spark reporting sustained factor VIII levels of 12% and 14% in two patients. These levels are high enough to prevent spontaneous bleeds. This brings up the question: what level of factor expression represents a cure? Should we wait until gene therapy can cure hemophilia by raising factor levels above 50%? And of course, the question of cost is forefront in everyone’s mind. These questions have yet to be answered.
The times they are a changin’! Never before have we had so many factor products on the market, with new factor products, as well as disruptive small molecules and gene therapy, still in development. What is certain is that, in the near future, hemophilia therapy will look dramatically different than it does today.
1. https://www.techopedia.com/definition/14341/disruptive-technology