Hypoparathyroidism: rare endocrine disorder garners attention from biopharma in 2024

Hypoparathyroidism is a rare condition in which the body produces abnormally low levels of a hormone called the parathyroid hormone (PTH), which is key to regulating and maintaining a balance of calcium and phosphorus in the body. People with hypoparathyroidism have a higher risk of developing chronic kidney disease. While hypoparathyroidism may not be known to many, the treatment landscape has made quite a buzz this year with a major drug approval, acquisition, and significant advances in clinical trials.

Yorvipath: first hormone treatment for hypoparathyroidism bags FDA approval

The big news for the space came when the first-of-its-kind hormone treatment Yorvipath was greenlit by the U.S. Food and Drug Administration (FDA) in August. Yorvipath, owned by Danish biotech Ascendis Pharma, is given as an injection under the skin using a pre-filled pen. It contains the active substance palopegteriparatide, which converts into teriparatide, a shortened form of PTH, once inside the body. Teriparatide essentially replaces the missing PTH as it enters the tissues in the bones and kidneys to help restore calcium levels. 

“The consequences of hypoparathyroidism on the health and quality of life of our patients can be extraordinarily debilitating,” said Lynn Kohlmeier, chair of the Medical Advisory Board of the HypoPARAthyroidism Association, and an investigator in Yorvipath’s clinical trial. “The ability to address the underlying cause of this disease is crucial and will be an important advancement for our patients with hypoparathyroidism.”

The approval was a hard-fought one for Ascendis. The drug was shot down twice by the FDA before its eventual launch. The biotech received the much-dreaded complete response letter – a notice rejecting approval of a drug in its current form – from the FDA, which cited manufacturing concerns, last year. Then, the FDA delayed its decision earlier this year, until August when it was finally approved.

This approval was based on its promising performance in the clinic. Phase 3 trial results from 2022 showed that Yorvipath – also known as TransCon PTH – showed a response rate of 78.7% in patients with hypoparathyroidism where calcium was restored to normal levels compared to 4.8% in the placebo group. 

All primary and secondary endpoints were met and the drug was well-tolerated. Side effects were experienced by 82% of those in the treatment group and all of the patients in the control group. One patient died from a fatal cardiac arrest, which was unrelated to the clinical trial, a report confirmed.

Patient perspectives: Yorvipath approval is a key milestone

Now that Yorvipath has hit the market in the U.S., the hypoparathyroidism community has lauded its effectiveness. In an article by Endpoints News, Michele Rayes, associate director at the HypoPARAthyroidism Association in the U.S., who has had the condition for three decades, said that it feels like she doesn’t “have a disease anymore,” and that she can now do daily activities that she hasn’t “done in decades.”  

This is a considerable step up from taking 64 pills a day to manage the condition, Rayes recounted. One of the medications Rayes was on was Takeda’s Natpara, which she said wasn’t helping much. The drug’s short half-life meant that patients had to rely on vitamin D and calcium supplements to get through the day. The drug was recalled five years ago when reports of rubber particles from the rubber septum leaking into the cartridge containing the therapy caused worry. The recall was lifted but Natpara is now being discontinued, Takeda revealed in a press release.

Yorvipath’s clearance is said to be a big deal for patients with hypoparathyroidism in the U.S., which is estimated to affect around 70,000 in the country, according to a report by the National Organization for Rare Disorders. Patty Keating, executive director of the HypoPARAthyroidism Association, expressed that the drug would greatly benefit patients.

“FDA approval of Yorvipath is such an important milestone for our community,” said Keating. “We are thankful that the seriousness of our condition has been understood and our voices heard. We look forward to having this new treatment option to help us move beyond the limits and risks of conventional therapy.”

On an IPO high: MBX and Septerna to boost hypoparathyroidism treatments in clinic

Meanwhile, riding on the second initial public offering (IPO) wave this year, MBX Biosciences and Septerna Therapeutics have stirred the biotech industry and the hypoparathyroidism treatment space alike. U.S.-based MBX’s $187.7 million offering will fund its lead candidate MBX 2109 – hoping to take on Yorvipath – into phase 3 studies.

The IPO was following the news of the first patient being dosed in a phase 2 trial testing MBX 2109. The drug candidate is born from the American biotech’s platform that is designed to tackle the drawbacks of protein therapies. One of these is short half-lives – as seen with Natpara – meaning they are quickly degraded by enzymes in the body and swiftly cleared out. MBX believes it has cracked the code to this challenge. 

It has pioneered precision endocrine peptides (PEPs) with the aim of extending the drugs’ half lives and reducing the frequency of dosing. The injectable MBX 2109, which is a PEP, is a PTH peptide prodrug that gets activated when it binds to the protein albumin in the body.

“We are pleased to advance our innovative PEP candidate MBX 2109 by dosing our first patient with hypoparathyroidism,” said Kent Hawryluk, president and chief executive officer of MBX Biosciences, in a press release. “The phase 1 findings for safety, pharmacokinetics, and pharmacodynamics support the potential of MBX 2109 as the first once-weekly PTH prodrug for hypoparathyroidism, and initiation of patient dosing brings us closer to launching our potential PTH therapy.”

Topline results are expected to be released next year, Hawryluk added. 

Following MBX’s IPO, Septerna went public after it closed a $331.2 million offering last month. Its phase 1 drug SEP-786 is a G-protein coupled receptor (GPCR) therapy – the largest and most diverse group of membrane receptors in the body that the PTH1 receptor (PTH1R) belongs to. It is in development to address all patients with hypoparathyroidism. This includes the most severe patients, who may start injectable PTH peptide therapy, as well as mild-to-moderate patients who are currently on high doses of calcium and vitamin D and may be less interested in an injectable PTH peptide, explained a spokesperson from Septerna.

“The majority of the other product candidates in development for hypoparathyroidism are injectable PTH peptides. To our knowledge, SEP-786 is the only clinical-stage oral small molecule PTH1R agonist,” said Septerna’s spokesperson.

The drug activated PTH1R and regulated the main genes responsible for maintaining calcium balance in the body in a manner similar to native PTH in preclinical studies. Moreover, in a rat model that had undergone a surgery called thyroparathyroidectomy – which involves the removal of the thyroid and parathyroid glands – that replicates hypoparathyroidism in humans, SEP-786 increased vitamin D levels and helped balance serum calcium and phosphate levels over 28 days.

“We believe there is an unmet need for an oral small molecule PTH1R agonist that offers hypoparathyroidism patients a convenient, more physiological treatment option. Since conventional therapies such as calcium and vitamin D have limitations and do not restore other actions of PTH, such as bone turnover or renal calcium reabsorption, we believe an oral option that can increase serum calcium and replace the other functions of PTH is needed for patients,” said Septerna’s spokesperson.

AstraZeneca nabs AZP-3601 in $800 million Amolyt buyout

As R&D makes headway, big pharma has also recently recognized therapeutic potential in hypoparathyroidism. AstraZeneca’s acquisition of French biotech Amolyt Pharma in March is telling of this. It paid $800 million to get a hold of Amolyt’s lead candidate AZP-3601, another peptide drug in the clinic to treat the disease. Like Septerna’s SEP-786, Amolyt’s drug is a peptide agonist of the PTH1 receptor but is instead given as an injection. 

A phase 2 trial showed that 93% of patients who were treated with AZP-3601 were able to discontinue standard of care therapy of calcium and vitamin D supplements while maintaining mean serum calcium within the required range. The drug landed the FDA’s fast track status and is set to report phase 3 topline data next year.

“We look forward to maintaining a constructive dialog with the agency as we work to bring new hope to patients suffering from this rare but challenging endocrine disorder as efficiently as possible,” Thierry Abribat, founder and chief executive officer of Amolyt Pharma, had said in a press release.

The approval of Yorvipath is an important first step in the hope that people with hypoparathyroidism will soon have a range of treatments to meet their needs. The drug, which is currently available in Germany and Austria, will reach patients in the U.S. early next year. And now that the drug met primary and key secondary endpoints in a phase 3 study done in China – licensed to Visen Pharmaceuticals – it won’t be long before it enters Chinese drug markets and possibly other parts of the world.

New technologies related to hypoparathyroidism

• Use of Calcilytics for Preventing or Treating Hypoparathyroidism Associated with Anterior Neck Surgery – Medical University of Vienna