While it was technically successful, BridgeBio Pharma, Inc.’s Phase I/II study of its gene therapy BBP-631 in congenital adrenal hyperplasia (CAH) did not quite deliver a strong enough result to justify continued investment. BridgeBio is planning to partner the asset out while making steep cuts to its gene therapy program.
The hub-and-spoke biotech announced 10 September topline results from the Phase I/II Adventure trial of BBP-631, an adeno-associated viral vector (AAV) 5 gene therapy. The trial was designed to test safety, tolerability and pharmacodynamics in adults with classic CAH. But while the gene therapy produced an increase in endogenous cortisol production in higher dose cohorts, which the company said was the first time that result was seen in CAH patients, it said the data do not warrant additional capital investment at this time, though it did not specify what threshold it had hoped for.
Key Takeaways
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BridgeBio said it would stop development of BB-631 for CAH after results of a Phase I/II trial did not meet the threshold for continued capital investment.
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The company is also planning to cut $50m from its gene therapy development program and fine tune its focus.
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An analyst said the move could give Spruce Biosciences a stronger chance of making its Phase IIb tildacerfont the second CAH drug to market, behind Eton’s already approved Alkindi Sprinkle.
As such, it is reducing its gene therapy budget by more than $50m and will no longer pursue development of BBP-631 in CAH, planning instead to seek partnering opportunities to support future develop of the asset or of next-generation therapies for CAH. It said the spending cut is consistent with its capital allocation principles and strategy of reserving gene therapy for priority targets it cannot treat any other way.
The same day, BridgeBio said the US Food and Drug Administration had granted it a regenerative medicine advanced therapy (RMAT) designation for the other gene therapy listed in its pipeline, the Phase I/II BBP-812, an AAV9 gene therapy for Canavan disease. The company said the FDA gave it the RMAT designation after reviewing clinical data from the Phase I/II CANaspire trial.
CAH is a group of genetic disorders that affect about 75,000 people in the US and EU and affect the adrenal glands, resulting from a mutation in the gene encoding for 21-hydroxylase, an enzyme essential for making the hormones cortisol and aldosterone. Cortisol is necessary for responding to stress, injury or illness, while aldosterone helps maintain blood pressure and sodium levels.
Gene Therapy Good, But Not Good Enough
BridgeBio reported that all patients receiving higher doses of BBP-631 showed increased endogenous cortisol production, with a maximum change from baseline after ACTH stimulation test of 4.7mcg/dL and 6.6mcg/dL observed at the two highest dose levels, and patients achieving cortisol levels as high as 11mcg/dL.
Also reported were substantial and durable increases in 11-deoxycortisol, the product of 21-hydroxylase and reductions in 17-hydroxyprogesterone, the substrate of 21-hydroxylase, which BridgeBio said provide compelling evidence of durable transgene activity from BBP-631. There was an average 55-fold increase in sustained 11-deoxycortisol from baseline, with a maximum 99-fold increase, representing an average maximum of 23-fold the upper limit of normal. In 17-hydroxyprogesterone, most patients had at least a 50% reduction, with 95% being the greatest reduction.
In terms of safety and tolerability, only mild treatment-emergent adverse events were reported, with none that were considered serious and related to treatment.
Still, the company said, the data are “not yet transformational,” though they do indicate for the first time that patients living with CAH can make their own cortisol and that they can safely receive gene therapy.
In a 10 September note, Leerink Partners analyst Mani Foroohar said the reaction to the news would likely be modest, “given [BridgeBio’s] plan to partner for programs not meeting their capital threshold has been telegraphed for some time.”
Shares of BridgeBio closed down 6.7% at $27.99 on 11 September.
In a same-day note, JMP Securities analyst Jonathan Wolleben said that although the gene therapy “was a long shot,” BridgeBio falling out of the race is an incremental positive for Spruce Biosciences, Inc., which jumped from third in line to having its Phase IIb tildacerfont potentially be the second CAH drug to win approval, after Eton Pharmaceuticals, Inc.’s Alkindi Sprinkle (hydrocortisone oral granules), which the FDA approved in 2020. (Also see "Major Milestone For Diurnal As FDA Approves Alkindi" - Scrip, 30 September, 2020.) Spruce licensed tildacerfont from Eli Lilly and Company in 2016. (Also see "Start-Up Spruce Repurposes Lilly Drug For Genetic Adrenal Condition" - Scrip, 8 March, 2019.)
“We remain cautiously optimistic that the make-or-break readouts for tildacerfont next quarter could look good and we continue to like the opportunity for tildacerfont in CAH, which affects ~20K-30K patients in the US today with ~250 patients identified via newborn screening annually, which is large enough to support multiple drugs,” Wolleben said. “While a one-and-done option for CAH is appealing, it does not appear the science is quite there yet, with BBIO stating that the Phase 1/2 data were ‘not yet transformational’ but do support the candidate’s safety profile.”
