Controversial dwarfism drugs spur growth — but do they improve health?

Until an ultrasound scan at 20 weeks, Samantha Anderson’s second pregnancy had been going according to plan. That scan revealed that her baby had some excess fluid in their skull. The physician wasn’t too concerned, but he asked Anderson and her husband Mike, who live in Merced, California, to come in for another ultrasound in the third trimester, just to be safe.

It was at that next appointment that Mike Anderson remembers getting worried. “The ultrasound tech started getting quieter and quieter as she measured and remeasured,” he says. The physician couldn’t make an official diagnosis, but she suspected that the Andersons’ baby might have a type of dwarfism. Mike remembers feeling overwhelmed by the uncertainty. He and Samantha had discussed so many what-ifs. This was not one of them.

After the baby, named Liberty, was born, physicians took a sample of umbilical cord blood and sent it for genetic testing. Liberty has achondroplasia — the most common form of dwarfism — which affects about 250,000 people worldwide. It arises from a mutation in a single gene that plays a crucial part in bone growth, and that results in an average adult height of 124–132 centimetres. Parents can pass the condition on to their children, but in most cases the mutation arises spontaneously. Eighty per cent of people with achondroplasia, like Liberty, are born to parents of average height.

For generations there has been no treatment, but that changed in 2021 with the approval of Voxzogo (vosoritide) for children aged five and over by the US Food and Drug Administration (FDA), and for those aged two and older by the European Medicines Agency. The drug helps children with achondroplasia to grow taller by targeting the molecular pathways responsible for the condition. Now, four other drug companies have related compounds in late-stage clinical trials. Meanwhile, the maker of Voxzogo — BioMarin in San Rafael, California — is seeking approval to extend its treatment to younger children and infants in the United States and Europe.

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The treatments have been controversial. Their approvals hinge on the drugs’ ability to make children grow taller, faster. And although a few extra centimetres might make it easier for people with dwarfism to manage in a world built for taller people, “height is not a medical problem”, says Andrea Schelhaas, a genetic counsellor at the Skeletal Dysplasia Program at Nemours Children’s Health in Wilmington, Delaware, who works with people who have achondroplasia and has the condition herself.

Many dwarfism advocates and the families of children with achondroplasia are eager to know whether the drugs improve health by addressing the complications that can accompany the disorder and are sometimes life threatening. These include sleep apnoea, ear infections, pinched spinal cords and the build-up of fluid in the skull. Answering that question, however, could take years, or even decades.

In the meantime, many people around the world are clamouring for access to the new treatments. Disability advocates worry that parents of average height, such as the Andersons, will make a treatment decision out of fear, without understanding what it means to live with achondroplasia. Liberty, who is 4 years old and shorter than her 18-month-old sister, could be eligible to begin Voxzogo as early as October, when the FDA might allow younger children to take it. “For an average-height parent, this may be the first person with dwarfism they’ve ever known — their own kid,” says Kara Ayers, associate director of the University of Cincinnati Center for Excellence in Developmental Disabilities in Ohio who has a form of dwarfism called osteogenesis imperfecta.

Parents are left with a tough choice that they must make on behalf of their children, and on the basis of incomplete data. “It’s more nuanced, I think, than a lot of people realize,” Ayers says.

Open tap

Dwarfism is a catch-all term for short stature caused by one of more than 300 genetic conditions. Scientists uncovered¹ the genetic cause of achondroplasia in 1994. In nearly all cases, it is the same variant, a single nucleotide substitution in the gene that encodes a protein called fibroblast growth factor receptor 3 (FGFR3).

FGFR3 restricts the growth of many bones. When functioning normally, it binds to proteins called growth factors and curbs the proliferation and differentiation of chondrocytes, cells that accumulate near the ends of bones and create cartilage that eventually gets replaced by bone. The variant that causes achondroplasia keeps the receptor active most of the time. Ravi Savarirayan, a clinical geneticist and researcher at Murdoch Children’s Research Institute in Melbourne, Australia, likes to use the analogy of a garden hose. “It’s like a tap being left on,” he says — it floods the garden and hampers growth.

The most apparent effect of this overactive tap is on height. But there are other features. People with achondroplasia tend to have large heads with prominent foreheads. The condition also causes disproportionately short arms and legs, because the long bones in the limbs are where the growth differences are most marked.

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Achondroplasia also comes with many potential medical challenges. One of the most serious involves the opening at the base of the skull, called the foramen magnum. In young children with achondroplasia, this hole tends to be smaller than average. That creates a pinch point at which the brainstem and spinal cord might start to get squeezed. It can be fatal, says Janet Legare, a skeletal-dysplasia expert at the Waisman Center at the University of Wisconsin–Madison. Without screening, the risk of sudden death in children under the age of 5 with achondroplasia can be almost 50 times greater than it is for the general population.

About 20% of children with achondroplasia require surgery for this condition, which involves removing a portion of the skull and shaving off bone to widen the opening. This takes pressure off the brainstem and spinal cord.

Jade and Chris Akal found out that their son Archie needed this surgery in May 2022, when he was six months old. He didn’t have any symptoms, but a magnetic resonance imaging scan revealed that the opening was already so narrow that spinal fluid wasn’t flowing as expected. Jade remembers reading the surgical consent form and bursting into tears when she saw the dangers involved. “It’s either the operation, or you risk his life,” she remembers the neurosurgeon saying.

For Archie, the surgery was a success. But there is a chance he will need to have the opening enlarged again — as happens in 10% of children with achondroplasia who have this surgery. Or surgeons might have to operate on another pinch point lower down his back.

There are other health issues, too. FGFR3’s effects on cartilage tend to flatten the nasal bridge. Less space behind the nose and mouth increases the risk of sleep apnoea, breathing problems and ear infections. Children with achondroplasia can also have poor muscle tone, which means that it typically takes them longer than average to hit developmental milestones such as standing and walking. Archie started walking at 19 months old.

Gold rush

In the early 2000s, a treatment for achondroplasia started to look possible. Researchers at Kyoto University in Japan discovered that a protein called C-type natriuretic peptide (CNP) has an important role in bone growth². In a mouse model of achondroplasia, an infusion of CNP helped the animals’ bones to grow to lengths seen in unaffected animals.

Voxzogo is a CNP analogue. It doesn’t act on the FGFR3 garden tap itself, but binds to a different receptor that, when activated, interferes with one of the pathways that restricts bone growth. “It’s basically kinking the hose to allow more normal growth to resume,” Savarirayan says.

BioMarin began the first clinical trial of the drug in 2012. In 2018, when it was time to launch the trial that would be used to apply for regulatory approval, the FDA convened an advisory group to help determine how to evaluate the drug’s effectiveness. Advisers discussed a handful of metrics that might work, but landed on ‘annualized linear growth velocity’, a measure of the rate of change in height over the course of a year. Tracking this would be straightforward and reproducible, they argued.

Voxzogo’s regulatory approval is based on a year-long study in 120 children aged between 5 and 15 years old, with 2 years of follow-up³. Participants who received a daily injection of Voxzogo had grown, on average, 1.57 centimetres more at the end of the first year than did those who received a placebo. Because there are no other treatments for achondroplasia, Voxzogo was given the nod through the FDA’s accelerated approval programme. This means that BioMarin will have to continue studies to assess final adult height.

Several similar drugs are in the works. Ascendis Pharma in Hellerup, Denmark, is testing another CNP-like molecule, called TransCon CNP. In the body, the natural peptide is mopped up quickly by its receptor, so it doesn’t last long. “CNP is a tricky molecule,” says Kennett Sprogøe, chief research and product development officer at Ascendis. The firm linked its version of the peptide to a carrier that shields the binding portion of CNP, helping it to last longer. Voxzogo stays in the blood for just a couple of hours, which means that children need a daily injection. TransCon CNP is given weekly.

Ascendis launched its pivotal trial to evaluate the safety and efficacy of TransCon CNP in March. The 80-person trial, involving children between the ages of 2 and 11, will compare the effect on growth of a once-weekly injection of TransCon CNP with that of a placebo.

Other companies are taking a different tack, directly targeting the FGFR3 receptor itself (see ‘Therapeutic mechanisms’). At the biotechnology firm BridgeBio in Palo Alto, California, researchers are testing a compound called infigratinib. The molecule binds to FGFR3 and inhibits it. If Voxzogo kinks the hose, infigratinib turns down the tap.

Infigratinib was originally approved as a cancer therapy, because FGFR3 is hyperactivated in some cancers. For achondroplasia, the company uses a very low dose. The goal is to “lightly tap the brakes instead of slamming the foot down”, says Justin To, chief operating officer of BridgeBio’s skeletal dysplasia programmes.

Tyra Biosciences in Carlsbad, California, and Sanofi in Paris are working on other approaches. Tyra is developing an oral FGFR3 inhibitor — TYRA-300 — initially for bladder cancer and solid tumours. In March, the company announced it will also be testing it as a treatment for achondroplasia, with plans to launch a phase II trial in 2024. Sanofi is targeting FGFR3, too, but with an antibody that binds to the receptor and might block the natural growth hormone from binding or otherwise prevent it from working properly.

Differing views

Many families have been eagerly awaiting these treatments. When Roon van Rhee found out that his daughter, Lieve, had achondroplasia soon after she was born in 2015, he rushed online to research the condition. He came across information about BioMarin’s clinical trial, but there weren’t any trial sites in Argentina, where he and his family live. In 2017, BioMarin reached out with an offer. The company could enrol Lieve in an observational study to track the course of the disease. She wouldn’t receive the drug, but it felt like a step in the right direction. “It was our contribution towards the development,” van Rhee says.

Lieve’s family hoped she would be able to start Voxzogo soon after it was approved in 2021, but getting their health-insurance company to cover the medication took more than a year of court battles. So, she wasn’t able to get her first dose until April. Van Rhee hopes it will help with some of the practical issues Lieve struggles with — reaching light switches, getting in and out of cars and washing her hair.

In Tbilisi, Georgia, parents of children with achondroplasia marched in the streets to demand that the government provide access to the drug, and some parents broke down in tears. “They want us to keep waiting and waiting,” said one mother. “There is no more time to lose.” In June, their wish was finally granted. An initial group of a few children will receive Voxzogo, paid for by the government, before the end of the year.

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BioMarin’s revenues from Voxzogo suggest that demand has been growing rapidly. With a cost of US$350,000 per year, Voxzogo brought in $19.7 million in the first quarter of 2022 — not long after it was approved. By the second quarter of this year, sales had jumped to $113.3 million. As of June, more than 2,000 children were taking the drug, and if BioMarin gets the green light from regulators in the United States and Europe for younger children and infants, another 1,000 would be eligible.

But for some, Voxzogo and the raft of therapies that might follow don’t feel like a win. These medications speed up growth, but many people with dwarfism don’t see being short as a problem that needs fixing. “People responded as if this was an attack on the subculture and the identity of people with dwarfism,” says Joseph Stramondo, a bioethicist at San Diego State University in California, who has another form of dwarfism. To some, it looked like erasure or even eugenics, says Jennifer Crumly, public-relations director for Little People of America (LPA), an 8,000-member advocacy organization in Sonoma, California, for people with dwarfism.

BioMarin has been in contact with the LPA for years, but the conversation has always been strained, Crumly says. “They consistently viewed our organization like a patient advocacy organization and not as a dwarfism advocacy organization. And those are two very distinct perspectives,” she says. Michael Hughes, chair of the LPA’s Biotech Industry Liaison Committee, remembers feeling as if BioMarin didn’t value the committee members’ input and would twist their words to fit the company’s objectives. “They’ve been very stubborn,” he says.

A representative for BioMarin responded to Nature by e-mail, stating that the company is working with Hughes and is “dedicated to fostering an open and empathetic conversation as we move forward together”.

The LPA knew that the therapies were a divisive issue. Still, when it accepted BioMarin as a sponsor of its annual conference in 2019, the intensity of the reaction caught the LPA’s leadership off guard. Some members organized a walkout. “The backlash by the community was assertive, and it was passionate, and it was honestly well deserved,” Crumly says.

The LPA no longer takes sponsorship money from pharmaceutical companies. Its current statement on Voxzogo reads, in part, “Our height-related challenges are primarily based on inaccessible architecture, lack of universal design, and society’s intolerance and discrimination of people with short stature. We are concerned that this recently approved drug attempts a pharmaceutical solution to a societal issue.”

Jonathan Day, a physician and head of late-stage clinical development at BioMarin, says that height was never the only goal of Voxzogo. “We didn’t develop this drug to purely enhance stature,” he says. Although it is not obliged by regulators to do so, BioMarin plans to look at how the drug affects proportionality, sleep apnoea, the incidence of surgical and medical interventions and changes in daily activities. It has already begun to look specifically at infants who are at risk of needing decompression surgery because of a small foramen magnum, so that it can assess whether Voxzogo helps to enlarge the opening.

“We’re thrilled with that study,” says Hughes. He would like to see more trials that look at factors other than height. “Those end points take longer to assess a benefit,” he says, but they’re also more meaningful to many in the achondroplasia community. Stramondo agrees. “If it does have an impact of some of these things, that absolutely changes the calculus for me,” he says. “Nobody is thinking that their spinal stenosis is essential to their identity and how they conceive of themselves in the world,” he says.

Early signs

Whether the drug will have an effect beyond height is not yet clear, but Savarirayan, who is lead investigator on many of the clinical trials, says that he’s already seeing hopeful signs. In 2021, he and his colleagues published data on children who had been taking Voxzogo for two years, and observed increased proportionality as well as height gains⁴. And, he says, children taking Voxzogo are finding it easier to dress and to clean themselves after using the toilet without a tool to help them reach. “That’s huge for the kids, really.”

In the Ascendis phase II trial of TransCon CNP, the researchers tracked adverse events — not only those potentially related to the treatments, but also problems related to achondroplasia, such as worsening snoring or curvature of the spine. In the placebo group, 9 out of 15 children had some achondroplasia-related adverse event during the treatment period. Only one out of 11 children taking TransCon CNP did. “This really caught our eye,” Sprogøe says.

Savarirayan has also presented promising unpublished data from the trial on the effect of Voxzogo on the size of the foramen magnum in children under the age of five, he says. That trial is expected to wrap up in 2027.

As the data begin to come in, Hughes says, he worries that BioMarin and people who consult for the company are trying to “connect the dots without drawing the lines”. Ayers says that parents are in a tricky position regardless of the data. “We say, ‘oh, parents will make the decision that’s best for their child’,” but they can’t just turn off their own perspectives, she says. “The parent comes with their whole baggage of life experience.”

Stramondo doesn’t blame parents who want their children to have the therapy. They’re living in an ableist society and doing what they think is best, he says. But he would like to see average-height parents try to understand what it’s like to live as a person with dwarfism, and to see them get involved in the community.

Beth Rooney, whose ten-year-old daughter Zoey has achondroplasia, did just that. She used to head her local LPA chapter near Philadelphia, Pennsylvania. Zoey has been taking Voxzogo since May. “I’m not trying to change her identity. We’re very happy that she’s a little person and love her just as she is,” Rooney says. But she knows that a few extra centimetres will make it easier for Zoey to navigate public facilities. Zoey, who swims competitively, wants to be able to stand in the shallow end of the pool.

The Akals aren’t certain what to do. They are worried about Archie’s future, whether the world will accept him and whether he’ll be bullied. “It’s so enticing to try something,” Jade says. But they’re also worried about long-term side effects. In South Africa, where they live, they would have to pay about US$10,000 a month for the drug, which is “not doable”, Jade says. Sometimes the decision seems so monumental that she’s grateful the drug is unaffordable for them, at least for now.

The Andersons say that their choice was an easy one. When Liberty was about two years old, they received an e-mail with information about a clinical trial for Voxzogo. Mike remembers googling the drug and talking to Samantha. But it didn’t take them long to come to a decision. “We just didn’t respond,” Anderson says. He and his wife, who were already deeply involved with the LPA, were concerned about the message they’d be sending to Liberty, that she was a child in need of fixing. “We would rather do the hard work of paving the road and working towards a future that is more accommodating for people with disabilities,” he says.

Liberty celebrated her fourth birthday in July, surrounded by friends and family at a princess-unicorn-mermaid pool party. “We’re dealing with a child who is living her fullest life right now,” Anderson says. “She walks into a room and her personality is 10 feet tall.”