Haemophilia is a mostly inherited genetic disorder that impairs the body's ability tomake blood clots, a process needed to stop bleeding.[2][3] This results in people bleedinglonger after an injury, easy bruising, and an increased risk of bleeding inside joints or thebrain.[1] Those with a mild case of the disease may have symptoms only after an accident or during surgery.[1] Bleeding into a joint can result in permanent damage while bleeding in the brain can result in long termheadaches, seizures, or a decreased level of consciousness.[1]
There are two main types of haemophilia:haemophilia A, which occurs due to low amounts of clotting factor VIII, andhaemophilia B, which occurs due to low levels of clotting factor IX.[2] They are typically inherited from one's parents through an X chromosome with a nonfunctionalgene.[6] Rarely a new mutation may occur during early development or haemophilia may develop later in life due to antibodiesforming against a clotting factor.[2][6] Other types include haemophilia C, which occurs due to low levels of factor XI, andparahaemophilia, which occurs due to low levels of factor V.[7][8] Acquired haemophilia is associated with cancers, autoimmune disorders, and pregnancy.[9][10] Diagnosis is by testing the blood for its ability to clot and its levels of clotting factors.[4]
Prevention may occur by removing an egg, fertilizing it, and testing the embryo before transferring it to the uterus.[4] Treatment is by replacing the missing blood clotting factors.[3] This may be done on a regular basis or during bleeding episodes.[3] Replacement may take place at home or in hospital.[11] The clotting factors are made either from human blood or by recombinant methods.[11] Up to 20% of people develop antibodies to the clotting factors which makes treatment more difficult.[3] The medication desmopressin may be used in those with mild haemophilia A.[11] Studies of gene therapy are in early human trials.[12]
Haemophilia A affects about 1 in 5,000–10,000, while haemophilia B affects about 1 in 40,000, males at birth.[2][5]
As haemophilia A and B are both X-linked recessive disorders, females are rarely severely affected.[6]
Some females with a nonfunctional gene on one of the X chromosomes may be mildly symptomatic.[6]
Haemophilia C occurs equally in both sexes and is mostly found in Ashkenazi Jews.[5] In the 1800s haemophilia B was common within the royal families of Europe.[5]
The difference between haemophilia A and B was determined in 1952.[5]
The word is from the Greek haima α?μα meaning blood and philia φιλ?α meaning love.[13]
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- Hemophilia A, a blood clotting disorder caused by a mutation of the Factor VIII gene and leading to a deficiency of Factor VIII. It was once thought to be the "royal disease" found in the descendants of Queen Victoria. This is now known to have been Hemophilia B (see below).[5][6]
- Hemophilia B, also known as Christmas Disease,[7] a blood clotting disorder caused by amutation of the Factor IX gene and leading to a deficiency of Factor IX. It is rarer thanhemophilia A. As noted above, it was common among the descendants of Queen Victoria.
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Sanofi's foothold in the hemophilia drug market is barely a year old but already looks shaky.
For two decades, drugs treating the rare blood disorder required multiple infusions each week. Among them were Eloctate and Alprolix, which the French pharma picked up through its recent $11.6 billion acquisition of Bioverativ.
But in 2017, hemophilia A patients got a longer-lasting option with Roche's Hemlibra. Given once-weekly and sometimes once-monthly, the drug's dosing schedule has already helped it draw sales away from rivals like Eloctate. Further disruption may not be far off, as analysts expect in 2020 the first approval decision for a hemophilia gene therapy, BioMarin's valrox, potentially offering type A patients a one-time treatment.
This rapid innovation puts pressure on Sanofi to show its newly constructed business isn't outdated. While the company is working on gene therapies too, they're preclinical and may come too late to be relevant.
Mani Foroohar, an analyst at SVB Leerink who covers genetic medicine makers, has argued that in rare diseases, it will be challenging for gene therapy latecomers to enroll clinical trials, because interested patients would most likely go for whichever one received regulatory approval first.
"It's very difficult to be the second curative product for a rare disease," he said.
Sanofi's lentiviral gene therapies likely won't be second either. In addition to valrox, a hemophilia A gene therapy from Pfizer and Spark Therapeutics and a hemophilia B gene therapy from UniQure have each advanced to late-stage testing. Pfizer and Sangamo Therapeutics are also partnered on an earlier-stage gene editing treatment for hemophilia B.
What patients prefer
Much depends on how quickly gene therapies make inroads.
Shannon Resetich, Sanofi's North American head of rare diseases and rare blood disorders, said she believes there's enough room on the market for multiple gene therapies, with adoption rates reflecting how safe, effective and durable each one is.
"This is an area that has a very personalized, individualized approach, and patient preferences sort of run the spectrum," she told BioPharma Dive in an April interview.
Based on conversations with physicians, Resetich expects hemophilia gene therapy will be adopted slowly.
Reni Benjamin, a former analyst with Raymond James, predicted gene therapies would capture about 30% to 50% of the hemophilia market. He said the percentage could go higher as patients, doctors and payers get more comfortable with the technology, though more traditional drugs from Roche, Sanofi and others will still hold pieces of the pie.
"No one ever gets 100% of the market," he told BioPharma Dive earlier this year, referring to the impact gene therapy could have in hemophilia. "There's always going to be some portion of the market, in my view, that just will not subscribe to it."
Last year, the Hemophilia Federation of America surveyed nearly 140 patients, caregivers and other hemophilia stakeholders. While results have yet to be published, the survey found a dichotomy regarding awareness and attitudes toward gene therapy, according to Meg Bradbury, the organization's research director.
Tracy Cleghorn is an officer at the HFA. The mother of a 16-year-old with the disease told BioPharma Dive she's excited by options with less frequent dosing.
She hesitates, though, to switch her son off Takeda's Advate, a drug he's taken nearly all of his life, without seeing more data.
"How am I going to know if it's not working? I'm going to know because he's going to have a bleed," she said. "And that's a tough way to know that something's not working, for your child to be hurt or in pain."
Despite the concerns, not everyone is convinced of a slow ramp up for gene therapies.
Financial services firm Cantor Fitzgerald says doctors seem to be very willing to prescribe valrox, based on a survey of 25 who, together, treat roughly 3,000 hemophilia A patients in the U.S. and Europe.
Published in early June, results from the survey found that, on average, 28% said they intend to prescribe the gene therapy to eligible patients within two years of its launch, and 39% said they would within five years. Cantor estimates about one-third of adult hemophilia A patients are eligible, and that the adoption rates seen in the physician survey reflect a peak sales opportunity of $1 billion to $1.5 billion.
Longer-acting agents a necessity
While the gene therapy story will take years to play out, it's clear hemophilia patients want some kind of longer-acting drugs.
Cleghorn of the HFA said she was initially very interested in how newer treatment options could benefit her son, who juggles high school and sports and will soon go off to college.
"If I could cut out any infusions, it's worth it," she said, adding that her son gets three Advate infusions per week, with each taking about five minutes.
Even a once-weekly treatment has been attractive for patients and their families. Roche reported in its first quarter earnings that more than 2,500 patients worldwide had started taking Hemlibra, leading to sales of 219 million Swiss francs for the period.
