Patisiran for hereditary transthyretin amyloidosis: lesser benefit than vutrisiran

Hereditary transthyretin-mediated amyloidosis, or hATTR amyloidosis for short, is a rare hereditary disease in which misfolded transport proteins from the liver form long fibres that are deposited in various organs. These deposits impair the functioning of organs such as the nervous system.

In addition to vutrisiran, which is administered as subcutaneous injection, patisiran, which is given intravenously and comes from the same manufacturer, is also approved for the treatment of patients with hATTR amyloidosis with stage 1 or 2 polyneuropathy.

As the turnover of patisiran with the statutory health insurance exceeded an amount of 30 million euros in the previous 12 calendar months, the manufacturer has now submitted a dossier on the drug’s added benefit versus the appropriate comparator therapy. In the dossier, the manufacturer compares patisiran exclusively with vutrisiran.

The Institute for Quality and Efficiency in Health Care (IQWiG) has now examined the advantages or disadvantages of patisiran compared to vutrisiran. Conclusion: Patisiran provides lesser benefit for patients than the appropriate comparator therapy vutrisiran.

Mirror image situation - with an unsurprising result

The approval study referred to by the manufacturer is the same one on the basis of which IQWiG assessed the advantages and disadvantages of vutrisiran compared to patisiran a good year earlier. In the HELIOS-A study, patients were treated with vutrisiran (subcutaneously, every three months) or patisiran (intravenously, every three weeks) for 18 months. At that time, the comparison was in favour of vutrisiran for several outcomes, so IQWiG's conclusion was: Vutrisiran has a minor added benefit compared with the appropriate comparator therapy.

Therefore, the assessment result was essentially logical in the current, mirror-image situation: For patisiran, there were only negative effects compared to vutrisiran, namely in patient-relevant outcomes on serious and severe adverse events. Therefore, there is lesser benefit of patisiran compared with vutrisiran for patients with hATTR amyloidosis with stage 1 or 2 polyneuropathy.

Do not reduce early benefit assessment to absurdity

The disadvantages of patisiran are not only statistically, but also clinically significant, as the manufacturer itself determined in its previous dossier. At that time, it emphasised the better safety profile of the subcutaneously administered drug vutrisiran - with roughly the same efficacy: Vutrisiran therapy was significantly less stressful for the affected patients.

Now it is trying to argue differently: The more frequent side effects, such as infections or cellulitis at the infusion site, mainly occurred at the start of treatment. At the same time, patisiran had been established in health care for years, and both physicians and patients were familiar with the safety profile. The manufacturer therefore sees a draw: no added benefit, but also no lesser benefit.

"If the soccer team 1. FC Köln won against the team of Bayern München, then Bayern München lost and didn't play to a draw - even if the Bayern squad would like it to be otherwise," says Thomas Kaiser, Head of IQWiG. Patisiran had only disadvantages compared to vutrisiran, the other drug from the same company. Consequently, it provides lesser benefit. “Any other conclusion of the assessment would render the early benefit assessment procedure completely absurd.”

G-BA decides on the extent of added benefit

The dossier assessment is part of the early benefit assessment according to the Act on the Reform of the Market for Medicinal Products (AMNOG) supervised by the Federal Joint Committee (G-BA). After publication of the dossier assessment, the G-BA conducts a commenting procedure and makes a final decision on the extent of the added benefit.

You can find an overview of the results of IQWiG’s benefit assessment in an English extract. In addition, the website informedhealth.org published by IQWiG provides easily understandable information on this benefit assessment.