Blueprint Medicines’ Ayvakit (avapritinib) is likely to displace its competitor, Novartis’ (SIX:NOVN) Rydapt (midostaurin), in advanced systemic mastocytosis (AdSM), experts said. They agreed FDA approval is a shoo-in. But off-label penetration in the much larger indolent systemic mastocytosis (ISM) market will be limited due to expected payer pushback, they said, until Phase II study results come in.

Ayvakit will replace Ryadapt in the AdSM market because of stronger efficacy, patient resistance to the latter, and the newer entry’s favourable side-effect profile, experts said. FDA approval is widely expected due to strong Phase II PATHFINDER results, they noted. Ayvakit has a 16 June PDUFA date.

Payers will likely decline off-label use in the ISM setting due to a lack of Ayvakit data in the indication and an expected price of more than $100,000, said experts. Its application in ISM will have to wait until the results of the Phase II PIONEER trial, they said. The trial’s primary completion date is this month.

ISM accounts for 95% of SM patients, according to a 25 February company presentation. One analyst report believes AdSM represents the biggest opportunity for Ayvakit but experts said, once approved, it could have strong traction in ISM, too. Sales for Ayvakit in SM are expected to reach $873m by 2027, according to GlobalData’s consensus forecast. A Blueprint spokesperson declined to comment, and pointed to company PRs.

Trumps Rydapt on efficacy

Ayvakit will replace Rydapt in AdSM patients because of its superior efficacy, said experts. The confirmed response of 75% demonstrated in the 62 patients with AdSM in the PATHFINDER will deliver benefits to more patients, said a source involved with the situation.

In its Phase II registrational trial, Rydapt produced an overall response in 59.6% of 16 patients with AdSM, according to the FDA label. There were also several complete responders in PATHFINDER, which is excellent as Rydapt has not been able to generate this in the past, said an investigator based in the western US. In the trial, complete remission with full or partial recovery of peripheral blood counts accounted for 18.8% of responses. In the Phase I EXPLORER trial, which was also included as part of Blueprint’s sNDA submission, complete response made up 35.8%, according to a 25 February company presentation.

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The vast majority of AdSM patients will have been treated with Rydapt, experts noted, with the figure likely to be upwards of 80%, said a US investigator based on the East Coast. It was a “game-changer” at its licensure when approved in 2017 but patients develop resistance and fewer patients respond to treatment, he said. In such cases, tryptase in a patient’s blood would start to increase, which is one of the easiest biomarkers to recognise resistance to Rydapt. The East Coast investigator tests tryptase levels in Rydapt patients at every visit and follows them every three months. The physical manifestations of Rydapt resistance include progression of allergy-like symptoms, worsening blood counts or an enlarged spleen or liver, he explained. Problems of resistance seem to be absent with Ayvakit so far, with the trial running for more than two years and no cases of resistance to the drug emerging, he added.

While there were safety events in the PATHFINDER trial, experts agreed these were manageable and that the drug has a more favourable safety profile to Rydapt. In PATHFINDER, intracranial bleeding occurred in 1.6% of 62 patients, according to the company presentation. Still, intracranial haemorrhage occurs in so few patients and is easily manageable by discontinuing treatment or boosting platelet count, said the western US investigator.

Grade 2 and higher cognitive events also occurred in 25% of AdSM patients, according to the same presentation. Events included confusion, memory impairment, and confused states, said the source. But this would not harm uptake as people are still functional and, in a setting where patients are highly symptomatic, they will accept AEs for disease and symptom control, he added.

On the other hand, Rydapt comes with a host of gastrointestinal (GI) AEs that make it poorly tolerated and hinder compliance, experts said. The most common adverse reactions, occurring in more than 20% of patients, include nausea, vomiting, diarrhoea, musculoskeletal pain, fatigue, and upper respiratory tract infection, according to Rydapt’s FDA label. Ryadapt’s oral capsule itself smells very bad and immediately causes patients to feel nauseous, while Ayvakit does not, said the source. Day to day, Rydapt is limited by its GI side effects in a way that Ayvakit will not be, said the East Coast PI, pointing to PATHFINER safety data that showed less than 15% of patients had AEs such as nausea, diarrhoea, and vomiting.

In terms of FDA approval prospects in AdSM, it is supported by strong efficacy and a positive risk-benefit ratio, the East Coast investigator said. Strong PATHFINDER data and the fact that AdSM is a deadly disease with only Ryadapt approved will lead to approval, said the source.

Off-label application limited by data and price

Payers will likely decline off-label use in ISM until Ayvakit has results in the PIONEER trial, experts said. On 12 May, this news service reported that the trial was enrolling speedily, with few entry barriers. Rydapt is also not commonly used off-label in ISM because of a lack of data and high cost, with its application limited to less than 5% of patients, the East Coast investigator said. Possibly, a maximum of 10% of patients could access it off-label with the help of physicians, said the Western investigator. If doctors argued that their patients are not responding to supportive care and need other treatment options, it could convince payers, but this is hard to do, he added. Insurers often resist when there is no published clinical trial data, especially with high-cost agents, and the East Coast investigator would expect pushback to off-label Ayvakit in ISM until data is available.

In Germany, patients would have a big hurdle to access as Ayvakit will be very expensive, so the insurers will likely not approve off-label use, said the source. While the company has not given any indication of how Ayvakit might be priced, it will likely be on par with Rydapt, which ranges from $50,000 to $125,000 a year, said the East Coast investigator. In AdSM, the price could be at the higher end of that range, in line with Rydapt, while in ISM there could be more resistance to the topline price, he said. This could be due to chronic use for symptom control and in an indication that does not definitively shorten survival, he explained. Tyrosine kinase inhibitors (TKI) like Rydapt and Ayvakit are extremely expensive, and can cost $100,000 to $250,000 a year, said the western US investigator, adding this would increase payer pushback.

According to Blueprint, the ISM market accounts for 95% of SM patients, although the East Coast investigator puts the figure close to 75%. While one analyst report stated Ayvakit will be most successful in the AdSM market, experts said it could have strong traction in ISM if approved. In ISM, patients are treated with supportive care to manage symptoms, with antihistamine use being a standard of care globally, said the East Coast investigator. About 50% of patients are easily managed with supportive care, said the western US investigator. The other half range from having some symptoms to living with a high level of symptoms, which seriously reduces their quality of life, he said. Ayvakit could represent an effective therapy for these patients, he added.

Sean Rai-Roche is a Healthcare Reporter for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.