Phase III Success For Roche’s Crovalimab In Crowded PNH Market

Roche is looking to challenge AstraZeneca's dominance in PNH with its subcutaneously administered once-a-month treatment but could struggle to rival the company's and Novartis’s oral therapy.

Roche expects to file crovalimab shortly and expects a US FDA approval by late 2023/ early 2024.

Roche has unveiled positive topline results from a non-inferiority study in paroxysmal nocturnal hemoglobinuria (PNH) between crovalimab and AstraZeneca’s blockbuster incumbent, Soliris (eculizumab).

AstraZeneca’s rare disease division Alexion has dominated the PNH market for years and its anti-C5 monoclonal antibodies Soliris and Ultomiris (ravulizumab) are set to chalk up 2022 sales of around $4bn and $2bn, respectively, across multiple indications.

Roche wants to improve on those first- and second-generation C5 inhibitors with crovalimab. It is a novel anti-C5 monoclonal antibody that has a ‘recycling’ mechanism which enables low-dose subcutaneous administration every four weeks. The drug also binds to a different C5 binding site from the Alexion treatments, which could help people with certain C5 gene mutations who do not respond to the current therapies. 

Roche reported the topline success from the Phase III COMMODORE 2 study, which compared crovalimab, given as a subcutaneous injection every four weeks, to intravenous doses of Soliris every two weeks in around 200 PNH complement inhibitor-naive patients.

The study looked at the drugs’ impact on transfusion avoidance and control of the ongoing destruction of red blood cells after 25 weeks, and Roche has reported that its candidate met both co-primary endpoints and was non-inferior to Soliris.

However full data will not be available until a forthcoming medical congress, so indications from safety and efficacy data where crovalimab may have an edge will have to wait.

Roche also has results from a separate Phase III COMMODORE 1 study in people with PNH switching from currently approved C5 inhibitors to crovalimab, and said this would be combined with the COMMODORE 2 results in a filing with regulators in the coming months. That could pave the way for US Food and Drug Administration by late 2023 / early 2024 which would help boost what is otherwise predicted to be a rocky year for Roche.  (Also see "Continuity Or Change? Roche’s New CEO And Pharma Leader Take On Big Strategy Question" - Scrip, 2 Feb, 2023.)

 

The Basel, Switzerland-headquartered firm is targeting a broad range of complement-mediated conditions with crovalimab, which is currently in five ongoing Phase III studies – PNH, aHUS, sickle cell disease and other complement-mediated diseases.

But it is just one of many companies looking to take a bite out of Alexion’s market. Already competing is Apellis Pharmaceuticals’ Empaveli (pegcetacoplan), which was launched in 2021 in the US and in Europe as Aspeveli and co-marketed with Sobi.

Apellis’s drug is approved in treatment naive as well as -experienced patients, with the latter being the main source of revenues to date ($45m in first nine months of 2022). This is likely to change thanks to the successful PRINCE study in treatment-naive patients, with the FDA expected to green-light a label update later this month.

Novartis Ready With Oral Rival

Another company expected to join the PNH fray shortly is Novartis with iptacopan. This is a potential first-in-class oral elective factor B inhibitor of the alternative complement pathway.

In December, Novartis unveiled results from its Phase III APPLY-PNH trial, which met both primary and most secondary endpoints. The results showed that iptacopan provided transfusion-free hemoglobin-level increases in the vast majority of adult PNH patients with residual anemia despite prior anti-C5 therapy.

The company has also recorded positive results in complement-inhibitor-naive patients in its APPOINT-PNH Phase III study, and will submit both studies for its filing with regulators later this year.  (Also see "Novartis Excited About Iptacopan But Downcast After Huntington’s Blow" - Scrip, 2 Feb, 2023.)

Nevertheless, some observers have predicted that AstraZeneca’s dominance will not be broken down rapidly. Analysts at Cowen said in a recent note that iptacopan's uptake in anti-C5 naive and clinically stable patients on Soliris or Ultomiris was “likely to be minimal in the short term.”

However, they did forecast Novartis’s drug being a potential best-in-class first-line oral complement inhibitor monotherapy, thanks to the positive results from its twin Phase III studies.

AstraZeneca is not standing still, however, and has two oral factor D inhibitors, danicopan (ALXN2040) and vemircopan (ALXN2050), in development for PNH and other complement-mediated conditions.

Danicopan is being studied as an adjunct to Soliris or Ultomiris in PNH patients whose condition causes extravascular hemolysis (the destruction of red blood cells in certain organs), despite being on Ultomiris or Soliris.

Around 40% of PNH patients remain anemic despite C5 inhibitor treatment because of the accumulation of opsonized cells, causing extravascular hemolysis (EVH). In September 2022, the company announced an interim analysis of the ALPHA Phase III trial of danicopan as an add-on to Ultomiris or Soliris showed positive high-level results in patients with PNH who experience clinically significant EVH.

Analysts at Deutsche Bank forecast that vemircopan could match Novartis’s drug and help AstraZeneca maintain its dominance in the field; this will be determined by the success of the two drugs’ rival mechanisms, factor D versus factor B inhibition.

‘Pipeline In A Product’ Battleground

PNH is just the largest of a broad range of complement-mediated immune disorders where competing companies are trying to meet unmet need.

Alexion has successfully expanded its original licenses in atypical hemolytic uraemic syndrome and PNH into generalized myasthenia gravis. Ultomiris is expecting an approval in neuromyelitis optica spectrum disorder later this year and is in Phase III for hematopoietic stem cell transplantation-associated thrombotic microangiopathy.

Novartis was confident enough in iptacopan to last year forecast peak annual sales of $3bn, though the lion’s share of this may come from two other key indications, C3 glomerulopathy and IgA nephropathy, rather than PNH.

Bank of America analysts said in a recent investor note that they foresaw iptacopan peak revenues reaching as high as $4.1bn, with C3G accounting for $2.8bn, PNH around $600m and $700m in IgA neuropathy.

Novartis is expecting Phase III readouts this year for C3G and IgA nephropathy, but cautioned recently on slow recruitment in these studies.

For Roche, the forecasts are currently for more limited opportunities, with Deutsche Bank estimating risk-adjusted peak sales of $375m in PNH; a fairly modest return which the company would hope to supplement with other licensed indications.

A plethora of other companies are pursuing candidates in the field, such as UCB, which has zilucoplan, a subcutaneous peptide inhibitor of C5 inhibitor and rozanolixizumab, a monoclonal antibody targeting the neonatal Fc receptor in adults with gMG.

However while companies have been attempting a landgrab in the complement-mediated field, many have had to re-evaluate commercial opportunities. These include BioCryst, which recently dropped one of its two oral factor D inhibitors, BCX9930, while Novartis last week scuttled its Phase II study of iptacopan in membranous nephropathy.