Welcome to your weekly digest of approaching regulatory and clinical readouts. In less than a fortnight an FDA advisory panel will look at Spectrum Pharmaceuticals’ bladder cancer project Qapzola, whose phase III results suggest that US approval will be far from a slam-dunk.
Meanwhile, Alnylam is targeting the rare disease primary hyperoxaluria type I with ALN-GO1 in the hope of having a product for which it can charge orphan prices. To get there it first needs the results from a phase I/II trial, which will come towards the end of this month, to be positive.
If the Qap fits
Spectrum has made a name for itself with targeted hits in oncology, and it is closing in on another potential US approval. The US FDA advisory committee will review the apaziquone application on September 14, and a final decision in December.
The Nevada-based group has proposed apaziquone, which it is branding Qapzola, in non-muscle invasive bladder cancer, where it is to be used immediately after surgical removal of tumours to prevent recurrence. Qapzola forms cytotoxic alkylating agents when reductase enzymes expressed by bladder tumour cells activate it.
A big reason for the agency to convene the adcom is that Qapzola failed to meet its primary endpoint of a significantly reduced rate of tumour recurrence at two years after the resection and treatment procedure in two separate phase III trials. A retrospective analysis pooled patients and found a difference, as well as a benefit in patients who had 30-90 minutes time to treatment with Qapzola.
Spectrum is in a third phase III trial under a special protocol assessment based on lessons learned from the first two. The study will evaluate intravesically administered apaziquone as a surgical adjuvant in patient undergoing transurethral tumour resection. The primary endpoint is time to recurrence with one instillation of 4mg apaziquone or two instillations of the same dose, versus placebo.
This study is not due to read out until 2020, however. The adcom will therefore presumably be guided by the failed trials, and forecast sales are understandably conservative: the sellside put 2022 sales at $59m, EvaluatePharma’s consensus data show, with $38m of this coming from the US.
Better oxalate than never
The annual meeting of the International Pediatric Nephrology Association might not be the biggest event held in Brazil this year, but it will at least be significant for Alnylam. The company is to present phase I/II data on ALN-GO1 in primary hyperoxaluria (PH) type I on September 24 at the congress in Iguaçu.
Patients with type 1 PH do not produce enough of the enzyme alanine-glyoxylate aminotransferase, which in healthy people metabolises glyoxylate into glycine and pyruvate. In the enzyme’s absence glyoxylate is converted to oxalate instead.
The subsequent accumulation of oxalate leads to a build-up of calcium salts in the kidneys and other organs, causing kidney stones and deposition of calcium oxalate crystals in the kidneys and urinary tract. The resulting impaired kidney function exacerbates the disease as oxalate enters systemic circulation where it can accumulate and crystallise in the bones, eyes, skin, heart, and central nervous system, leading to severe illness and death.
A different enzyme, glycolate oxidase, works one step ahead of alanine-glyoxylate aminotransferase, producing the glyoxylate in the first place. ALN-GO1 is an RNAi therapeutic that silences glycolate oxidase and therefore, Alnylam contends, reduces the amount of glyoxylate available to be mis-metabolised into oxalate.
The project is in a single-blind, placebo-controlled, phase I/II in healthy adults and patients with PH type 1 – 60 subjects in total. The primary endpoint is adverse events up to 181 days for single subcutaneous injections of ’GO1 and up to 321 days for multiple jabs.
Secondary endpoints include pharmacokinetic measures, levels of glycolate in the plasma and the excretion of glycolate and oxalate in the urine.
PH is rare, occurring in approximately two people out of a million, and ALN-GO1 has orphan status. A hit in phase II would bring Alnylam closer to getting a high-priced drug on the market.
|Phase III trial of intravesical apaziquone as a surgical adjuvant in 1,869 patients undergoing transurethral resection of bladder tumours||NCT02563561|
|Phase I/II trial of ALN-GO1 in 60 subjects, including healthy volunteers and patients with PH type 1||NCT02706886|