Natpar(a): A Case in Point for Rare Disease Drugs?

While the recent recall of injectable recombinant parathyroid hormone (PTH) (Natpara, Takeda) in the United States has grabbed the headlines, the situation for patients with chronic hypoparathyroidism who want to take the drug in Europe (where it's known as Natpar), and the rest of North America, is hardly any better.

Although the drug has not gone through the ignominy of being made available and then abruptly taken away as in the United States, patients in many countries, including the UK and Canada, never had access to it in the first place, creating "a lot of upset, angry patients."

For the manufacturer, the case of Natpara/Natpar highlights the difficulties of bringing drugs for rare diseases to market, and it believes the bar for evidence can be set far too high.

Hypoparathyroidism is a rare endocrine disorder. Standard treatment for hypoparathyroidism is active vitamin D or calcitriol (Rocaltrol, Roche) plus oral calcium supplements. However, for patients with severe hypoparathyroidism, injectable PTH is indicated.

The once-daily subcutaneous injectable recombinant form of PTH was approved by the US Food and Drug Administration in 2015 (as Naptara) and by the European Medicines Agency (EMA) in 2017 (as Natpar) for the treatment of adults with chronic hypoparathyroidism.

"Everything Was Going Great..."

Liz Glenister is founder, CEO, and chair of trustees at the charity Parathyroid UK, which works closely with professional societies and groups around the world and established World Hypopara Awareness Day.

She told Medscape Medical News that, as a result of the approval of the drug in the United States and Europe, patients "got very excited and thought, 'This is it!'"

"Of course, the American patients have been on it for some time now, in various forms and via various trials," she added, "and everything was going great."

Indeed, data from the long-term, open-label RACE extension study, published in April 2019, showed the drug was safe and effective over 6 years of continuous use. As reported by Medscape Medical News, results in 34 patients showed the drug was associated with a 40% reduction in oral calcium supplementation doses and a 72% reduction in calcitriol doses, while albumin-corrected serum calcium levels were maintained within target levels.

Consequently, the agent has so far been marketed in the United States, along with Denmark, Israel, Finland, Norway, and Sweden, and there was hope that it would become available in more countries in the near future.

That situation has now changed dramatically, however.

The drug was recently recalled in the United States following safety concerns over rubber particulate matter from the rubber septum of the drug's cartridge potentially contaminating the product.

The sudden withdrawal led to patients with severe forms of the disease being unable to adequately control their symptoms and, in some cases, being hospitalized because of severe hypocalcemia.

Glenister said this has "caused enormous grief and distress to [US] patients who have had to come off [Natpara] immediately, which is very difficult," and means many now have "huge problems," as described in an article on Medscape Medical News.

While the EMA did not withdraw the drug in response to the safety concerns, most patients with hypoparathyroidism in Europe still do not have access to the agent.

In the UK, as recently as February 2016, the National Institute for Health Research published a briefing document anticipating Natpar as a "new treatment option for patients with hypoparathyroidism that may reduce symptoms of the disease."

And in 2017, the National Institute for Health and Care Excellence (NICE), which determines whether drugs should be made available on the UK National Health Service (NHS), deemed it would be "appropriate" to conduct an appraisal of the drug, noting that up to 8400 individuals in England could receive it.

However, in February 2018, NICE suspended the appraisal and there has been no progress in making it available to NHS patients, despite isolated instances of healthcare services choosing to fund it.

Progress Stalled in UK; Patients Are "Upset and Angry"

Simon Meadowcroft, MD, Takeda Pharmaceuticals, UK, said while most patients are waiting for the NICE appraisal of Natpar to be reopened and for it to be funded by the NHS, it is possible for some to receive it.

"There are funding mechanisms available in the NHS for rare, occasional use medicines that aren't approved by NICE," he explained to Medscape Medical News.

These include pathways such as Individual Funding Requests (IFRs), which are considered on a case-by-case basis, and local funding decisions.

Meadowcroft added that some patients "may be able to access the drug privately but our focus is on making sure we get reimbursement so it can be used by that broader group of patients within the NHS."

For Glenister, the situation is hugely frustrating.

"We've been campaigning for this for a very long time now," she said, noting that they received good reports from patients taking part in the initial trials.

"From the patient's point of view, it was absolutely wonderful: 'like a lightbulb going on,' people said. And so we had great hopes and have been waiting for it ever since," she said.

But to find that the drug is still not available on the NHS is "incredibly disappointing, and there's a lot of upset, angry patients," she added.

Glenister continued: "The reason we need it is because the current therapy is not adequate; it was never devised for this condition and it can lead to quite severe renal outcomes."

And understanding the patient's condition is "very much guesswork on the part of the doctor and the patient, so it's a very difficult condition to manage," she emphasized.

Meadowcroft explained that the appraisal of Natpar was suspended because the EMA license was based on a "relatively small" phase 2 study and that the company does not currently have the "level of data required to get us over the bar with NICE."

This, he said, is "an example of the challenges that we and other companies are having with rare disease areas."

"The regulatory authorities accept that you will always have relatively limited datasets compared to more mainstream therapy areas," but it is "frequently not acceptable from a NICE perspective."

Glenister recognizes that has been an issue in hypoparathyroidism but also wondered whether the relatively high cost of the drug may also be an issue, as "local authorities won't...or can't pay for it."

Huge Variation in Where Natpar/a Is Available

Glenister said the situation is similar in Spain, where "a few people are getting it," but "it seems to be very much a postcode thing; if you're lucky enough to be in an area where they'll pay for it, you can get it."

There is, however, huge variation in the availability of Natpar across Europe.

Aside from a handful of countries where it has been granted market access, such as Germany — because there, once a drug is given regulatory approval, it is automatically made widely available to everyone who needs it — there are problems with access to Natpar in many places.

And in Canada the situation is different again — it's not a reimbursement issue, rather the drug has not yet been submitted for approval there. The drug is consequently unavailable except through clinical trials.

Aliya Khan, MD, a professor of clinical medicine at McMaster University in Hamilton, Ontario, Canada, has been involved in the global trial, and so her institution has some patients who receive it but, overall, "there are very few people on the drug" in Canada, she told Medscape Medical News.

She explained that the process for gaining regulatory approval and then market access in Canada is similar to that in the UK, albeit with greater acknowledgment of the limitations of diseases such as hypoparathyroidism.

"We recognize that, in these rare diseases, there just aren't enough patients to do the same level of robust trials as we have in disease states where many people are affected," she said.

"Once it's approved in Canada, if it's not available on a funded process then we can try to get compassionate release for our patients," Khan added.

She also does not believe that the drug price will hold back approval of Natpar in Canada, pointing out that "we have expensive drugs in other disease states."

For example, in osteoporosis, both teriparatide (also a form of PTH; Forteo, Lilly) and romosozumab (Evenity, UCB Pharma) are available in Canada, "so we have expensive drugs that are approved."

Khan said that, whatever the reason, the application for approval for Natpar/a "just hasn't happened yet."

"The plan was that an application was going to be made this year, I believe, and it will be made, I am 100% certain of that, next year," she said.

"I don't see that it would be a problem because we have very good evidence that this drug is beneficial and effective, and it's safe for patients," she stressed.

Takeda to Have Data for NICE in UK by Q3 2021; Patients Left "In Dark"

The question of the strength of that evidence is what is crucial in the UK.

Meadowcroft said that Takeda expects to have a data package sufficient to go back to NICE "probably around Q3 in 2021."

"You can't go back to NICE with sorts of odds and sods of data as you go along...We're not going to go back to them until we think we've got a decent chance, essentially," he said.

Alongside a phase 4 study, which is currently recruiting, there is an ongoing registry to collect real-world data, although Meadowcroft acknowledged that "clearly there's chicken and egg there, as the registry is only going to get populated by patients in situations where we've got reimbursement."

He continued: "I think the main point I would make is we are committed to making this available for NHS patients."

Beyond that, Meadowcroft believes the case of Natpar underlines the need for a number of changes in the way that healthcare watchdogs such as NICE approach market access decisions for drugs for rare diseases.

"We wouldn't expect funders to pay for these things without any sort of review," he said, adding he hopes NICE will develop a greater understanding of "the particular challenges in rare diseases and try to develop some pragmatic methodology."

"The other step that we as an industry always argued for is slightly greater coherence between the view NICE is taking and the view the regulators are taking," he added.

(In the UK, NICE may recommend a drug for use — making it more likely that health authorities will pay for it, and other countries also look to NICE for guidance — but it is the regulatory agency, either the EMA or possibly the UK-specific Medicines and Healthcare Products Regulatory Agency following Brexit, that actually approves a new agent).

In the longer term, Meadowcroft says it would be beneficial if NICE "were prepared to be more flexible around managed access schemes."

Although acknowledging this is a "challenging area," it is "perfectly reasonable to award a particular price based on the available data now and be prepared to review that a little bit down the line as further data emerges," he says.

In the meantime, Glenister said the lack of availability of Natpar has left her and other patients feeling "paralyzed" and "in the dark," a situation that will seemingly continue for the foreseeable future.

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