Since Fibrogen’s surprise win with pamrevlumab in idiopathic pulmonary fibrosis last year the rare lung condition has become a wild card to watch for in biotech pipelines. And Kadmon has become the latest to try to pull an IPF card from its sleeve, in the form of early data on its Rock inhibitor KD025.
While the signs are encouraging the data are very early – results in only 29 patients from an open-label trial have been disclosed – hence the 5% drop in Kadmon’s share price this morning after some initial enthusiasm. Executives promised to push on with bigger studies this year, but the company has a long way to go before real excitement is justified.
The biological rationale for targeting Rock kinases is pretty well established, and many believe that this mechanism holds real hope for treating fibrotic diseases. KD025, an inhibitor of Rock 2, essentially works by suppressing the differentiation of fibroblasts to myofibroblasts, a defining feature of fibrosis that in IPF leads to fatal damage to lung alveoli.
The question is whether Kadmon has a compound that can prove this theory, and naturally the company thinks it does. Patients treated with KD025 experienced a median decline in forced vital capacity of 48ml at 24 weeks, versus a decline of 175ml in those receiving best supportive care, Kadmon said, maintaining that the absolute difference of 127ml compares very favourably to Esbriet and Ofev, the only two FDA-approved drugs for this condition.
An important caveat is that Kadmon obtained its results over 24 weeks and IPF pivotal studies are conducted over 52 weeks – thus comparisons are hard to make at this stage.
|Company/study||Mean difference in FVC decline, active vs control|
|Kadmon: KD025 phase II (24 weeks)||127ml|
|Fibrogen: pamrevlumab phase II Praise study|
|ITT 48-week result||178ml|
|Projected 52 weeks||195ml|
|Boehringer Ingelheim: Ofev Inpulsis phase III (52 weeks)|
|Roche: Esbriet Ascend phase III (52 weeks)||116ml|
|Source: Company presentations, press releases.|
There are several other issues to bear in mind when looking at these data. Kadmon’s trial randomised 39 patients; however, of the 14 that went into the best supportive care arm, five crossed over to the active arm. And then seven withdrew owing to adverse events – only one of which was considered due to treatment – leaving only 29 subjects evaluable at 24 weeks.
Kadmon’s results are therefore not on an intent-to-treat basis – although the company contends that, however the data are cut, the same conclusions are supported.
It should also be remembered that in this trial Kadmon recruited patients who had previously received or had declined treatment with Esbriet and Ofev. This means that they had typically been living with an IPF diagnosis for much longer than those enrolled into the studies that won the Roche and Boehringer drugs their approvals.
Kadmon maintains that this is a real-world population – many patients chose not to try Esbriet or Ofev, both of which have substantial side effects. And many physicians would elect to get a patient enrolled into a clinical trial of a new agent ahead of these first-line agents, it claimed.
Neither Esbriet nor Ofev can halt the decline in lung function, and a huge proportion of patients eventually stop responding to these drugs.
Much to prove
On a conference call this morning Kadmon executives outlined plans to capture the whole market in future clinical studies. Within the next couple of months a larger second-line study will commence – this will be blinded and placebo-controlled, seeking 150 patients. And towards the end of the year a phase II study looking at KD025 in combination with existing agents will begin.
Liver enzyme elevation will be something to watch – one patient in the treatment arm of the latest trial exhibited a rise, echoing a signal seen in studies of KD025 in other indications. The company brushed off these concerns.
There is much room for improvement in IPF, and Kadmon itself has much to prove as well, of course, having disappointed investors since its 2016 IPO and being burdened with some controversial executive associations. With only $74m in the bank at the end of September it might have to hope that these data are sufficient to attract a partner with deeper pockets.