Hit and miss obesity data for Rhythm

The rare disease player plans to submit Imcivree in Bardet-Biedl syndrome next year, but Alström syndrome looks like a no-go.

With Imcivree’s approval in two extremely rare forms of genetic obesity in the bag, Rhythm Pharmaceuticals yesterday claimed a hit in the drug's pivotal trial in two more. But as its 5% share price fall suggests, all is not as it seems.

Firstly the data were somewhat disappointing, with the response rate in Bardet-Biedl syndrome falling far behind that seen in phase II, and no response at all among patients with Alström syndrome. And secondly, Rhythm based its claims of statistical significance by comparing against historical data rather than against the trial's placebo cohort. 

After a year’s treatment with Imcivree, a 10% reduction in bodyweight, the study’s primary endpoint, was achieved by 11 of the 28 patients with Bardet-Biedl but none of the three with Alström. This gave a statistically significant response rate of 35%, Rhythm said, giving a p value of 0.0024. 

Imcivree phase III data in Bardet-Biedl and Alström syndromes
Endpoint  Result at 1yr p value*
Percentage achieving 10% reduction from baseline in bodyweight (primary endpoint) 35% 0.0024
Mean reduction from baseline in bodyweight 6% <0.0001
Mean reduction from baseline in most hunger rating 31% <0.0001
Percentage achieving a reduction of at least 25% in most hunger scores from baseline  60% <0.0001
*All p values vs historical control. Source: company communications. 

But a p value requires a comparator – usually placebo or a recognised therapy for whatever disease the trial is in. And Rhythm’s study did include a placebo element: a 14-week randomised, double-blind, placebo-controlled period was followed by 38 weeks in which all patients received Imcivree; the primary analysis was then conducted.

The placebo group was not the comparator, however. Instead a Rhythm spokesperson told Evaluate Vantage that the trial had used a historical control response rate of 10% as the benchmark against which Imcirvee’s effectiveness was judged.

The historical control assumed that 10% of patients with Bardet-Biedl and Alström syndromes could lose 10% of their weight in one year. The figure was established in collaboration with Bardet-Biedl experts and the FDA, the company said.

“In that analysis, seven or more responders out of 33 would have been statistically significant. The final results were 11 of 31. Two study participants withdrew during the initial placebo-controlled period, and since they only received placebo and not active therapy [that] accounts for the difference in 33 and 31,” the spokesperson wrote. The analysis plan is detailed in an investor presentation dating from November.

Plans

Given the lack of response from the Alström syndrome patients, Rhythm said it has not decided on a plan for Imcivree in this indication. But it does intend to file the melanocortin 4 receptor agonist in Bardet-Biedl syndrome with regulators in Europe and the US in the second half of 2021.

This is the bigger of the two indications, with around 2,500 patients in the US and the same number in Europe. There are around 1,000 Alström syndrome patients worldwide. 

The question now is whether the drug’s showing in Bardet-Biedl will be good enough for approval. Stifel analysts were bullish, saying the response rate among Bardet-Biedl patients only was, at 39%, acceptable. Still, this was notably lower than the 67% response seen in phase II.

Moreover, 6% absolute bodyweight reduction after a year's treatment seems underwhelming, notwithstanding Rhythm's claim of significance. And the fact that the study comprises a mixture of patients, some of whom got 52 and others 38 weeks' active treatment, adds further complexity.

However, the FDA and other regulators seem unlikely to take issue with the comparison with historical data. Imcivree’s pivotal trials in obesity due to pro-opiomelanocortin or leptin receptor deficiency also used a historical comparator, though in this case the threshold was 5% of patients achieving up to 10% bodyweight loss over a year without Rhythm’s drug. Approval in those disorders came last month.

Stifel analysts model 2025 sales of $280m in Bardet-Biedl syndrome, compared with $136m in the two indications for which Imcivree is already approved.

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