TABLE. Ongoing or Announced Phase III rAAV-Mediated Gene
deleted) factor VIII protein that
maintains function.
Therapy Trials for Hemophilia A and B
As more pharmaceutical compa- Sponsor
Therapy
Coagulation Factor
nies develop their own gene transfer
BioMarin Pharmaceuticals Valoctocogene roxaparvovec (“val-rox”, formerly BMN-270)
Factor VIII
products for the treatment of he-
Spark Therapeutics
SPK-8011
Factor VIII
mophilia, the field is starting to get
Pfizer
Fidanacogene elaparvovec (formerly SPK-9001)
Factor IX
crowded. Dozens of gene transfer
UniQure
AMT-061
Factor IX
protocols have been approved by
the U.S. Food and Drug Adminis-
tration (FDA) over the years, more than a dozen experimental
The Unknowns of Gene Therapy
treatments are in phase I and II study, and four products have
“The big question for all gene therapy approaches for hemophilia
entered late-stage development in just the last few months.
will always be durability,” Dr. Pasi said. “The only way to answer
“My experience is that when you start to see many people
that question is to observe all of our patient cohorts over time.”
working along the same lines, it usually means things are work-
In human trials, the longest follow-up has been reported in pa-
ing,” said Dr. High.
tients with hemophilia B, and durability appears to be good at up
At present, BioMarin Pharmaceuticals, Spark Therapeu-
to eight years. In dog studies, long-term gene expression has been
tics, Pfizer, and UniQure all have gene therapy products being
noted for up to 10 years, “which is pretty much the lifespan of the
evaluated in phase III studies. The BioMarin and Spark products
dog, so it’s hard to have information beyond that,” Dr. George said.
are FVIII gene transfer products and the Pfizer and UniQure
Any hints of issues in durability or therapy-related adverse
products target FIX (see TABLE ). Each of these companies have
events can cause precipitous stock declines for companies
developing late-phase products. For example, BioMarin’s stock
reported factor activity levels returning to the normal range in
price slumped in May 2018, when new data on its candidate
patients with mild hemophilia in phase I and II trials, although
not all these data have been published in peer-reviewed journals. 2,3 product were released at the 2018 World Federation of Hemo-
philia World Congress. 7
In results from the Spark/Pfizer trial of gene therapy for
hemophilia B treatment with SPK-9001 resulted in a mean steady-
The data suggest a loss of effectiveness over time, which Dr.
state FIX coagulant activity of about 33 percent of normal two
George thinks may be a cause for some concern. However, Dr.
years after treatment. 4 Before treatment, FIX activity level was ≤2
Pasi, the primary investigator on this trial, explained that the
“gene-expression levels are stabilizing and following a pattern of
percent of normal in the 10 men treated. (Note: Pfizer and Spark
expression typically seen in many AAV systems.”
Therapeutics entered into a License Agreement in December 2014
Other questions that are still missing clear answers include
for the hemophilia B gene therapy program. In July 2018, Pfizer
the potential liver toxicity of these products, and the potential
assumed sole responsibility for all pivotal studies, regulatory
activities, and manufacturing and global commercialization of any for vector shedding. Also, approximately half of individuals
with hemophilia have pre-existing AAV neutralizing antibodies
products resulting from the program.)
(NAb), making them ineligible for gene therapy. Patients may
“At the 33-percent level of expression, most people do not
even develop AAV NAb after gene therapy.
bleed, and, indeed, the trial showed that the annualized bleed-
“The development of AAV NAb after vector infusion is par-
ing rate was reduced by close to 98 percent – even in people
ticularly important when considering extending this therapy to
who were already on standard-of-care management,” said Dr.
pediatric patients, who may require repeat infusion to accom-
High, senior author on that paper.
modate hepatic growth and expanded plasma volume,” said Dr.
In the early-phase trial of BioMarin’s gene therapy candi-
George. But, at this point, there is no clear solution to this issue.
date for hemophilia A, patients have maintained FVIII levels of
50 percent two years after infusion. 5
Dr. High suggested that it would likely take at least two
A Therapy for All?
years from the point a product entered phase III testing before
“Obviously, I am biased, and I think very optimistically about
a company could expect its candidate to be approved, “with an
gene therapy,” said Dr. George, “but if we can achieve predictable
upper bound of ‘who knows.’” For example, Spark’s voretigene
and durable expression, then, theoretically, this approach could
neparvovec-rzyl (indicated for the treatment of an inherited
help everyone.” However, there are some noteworthy barriers to
retinal disease) became the first gene therapy approved by the
achieving that goal – including that not all patients are eligible
FDA in December 2017 – a full five years after it entered phase
for trials.
III testing. 6
An estimated 20,000 individuals in the U.S. have hemophil-
ia, with hemophilia A being about four times more common
“It’s expected that the very first approval of a new class of
therapeutics will take longer,” she said, adding that, in hemophil- than hemophilia B. The worldwide incidence of hemophilia is
unknown but is estimated at more than 400,000 people. 8
ia, the endpoints for clinical trials are well known, while with
voretigene neparvovec-rzyl, “we had to develop and validate [the
Because hemophilia is an X-linked disorder, it is rare in
endpoints]” during the clinical study process.
women and, typically, they are excluded from trials because
“all of the pharmacology, toxicology, and vertical transmission
October 2018
17