Biogen Idec’s decision to bring STX-100 back home by purchasing Stromedix is a sign of transformation in the idiopathic pulmonary fibrosis (IPF) pipeline. Multiple setbacks in advancing treatments for this very sick population has sent drugmakers back into their laboratories to try more novel drug strategies.
The phase II pipeline is now dominated by biologicals (see table), as many of the small molecule approaches to reducing the characteristic inflammation of IPF have proved unsuccessful. Only one IPF candidate, Boehringer Ingelheim’s tyrosine kinase inhibitor Vargatef, is currently in phase III, but before it can report there is the potential for it to be joined by three antibodies in late stage testing.
|Idiopathic pulmonary fibrosis late stage pipeline|
|Status||Product||Generic Name||Company||Pharmacological Class||Proprietary Level 2||Trial IDs|
|Phase III||Vargatef||nintedanib||Boehringer Ingelheim||Tyrosine kinase inhibitor||NME||NCT01335464, NCT01335477|
|Phase II||CC-930||tanzisertib||Celgene/Ligand Pharmaceuticals||JNK inhibitor||NME + Orphan Drug||NCT01203943|
|STX-100||-||Biogen Idec/Stromedix||Anti-avb6 integrin MAb||NME||NCT01371305|
|CNTO-888||carlumab||Johnson & Johnson/MorphoSys||Anti-CLL2 MAb||NME||NCT00786201|
|FG-3019||-||FibroGen/Bristol-Myers Squibb||Anti-CTGF MAb||NME||NCT01262001|
|PC-SOD||midismase||LTT Bio-Pharma||Superoxide dismutase||NME||-|
|QAX576||-||Novartis||Anti-interleukin-13 (IL-13) MAb||NME||NCT01266135|
Biogen’s acquisition of privately held drug developer Stromedix for an initial payment of $75m brings back into its possession STX-100, an antibody Biogen outlicensed to Stromedix in 2007. Biogen paid $75m upfront with a promise of up to $487.5m in contingency payments to Stromedix’s investors based on development and approval milestones.
No matter what, the venture capital backers have gotten their investment back – the company raised a total of $31.4m in three funding rounds in six years of existence. However, its attempts last year to raise $15.5m in a third funding round a year ago to finance phase II trials of STX-100 were disappointing – it netted just $2m, although its existing investors loaned the company another $5m later in 2011.
Stromedix's funding difficulties may have been a sign of the general lack of enthusiasm for the space, since the twin disappointments in early 2010 of the failure of Tracleer in phase III trials (Actelionstopped in its tracks with negative Tracleer data, March 1, 2010) and the FDA’s rejection of Esbriet (Intermune left gasping by FDA rejection of pirfenidone, May 5, 2010), activity in IPF has ground nearly to a halt.
Prominent abandoned or suspended projects in IPF in the last couple of years include Gilead Sciences’ Letairis and Actelion’s macitentan.
Intermune did win European support, and Esbriet – sold also in the Far East by Shionogi under the name Pirespa – remains the only targeted drug for the disease, targeting the pro-inflammatory tumour necrosis factor alpha (InterMune receives welcome European approval gift for Esbriet, December 20, 2010). It is forecast to sell $474m in 2016, according to EvaluatePharma data.
But in the US patients have few options aside corticosteroids to reduce inflammation and supportive care, making it a disease crying out for novel therapies (Therapeutic focus - Behind Tracleer pulmonary fibrosis pipeline is a trickle, January 18, 2010).
A richer pipeline
In phase III, Boehringer Ingelheim’s Vargatef targets the tyrosine kinase signalling pathways shown to be involved in lung fibrosis – the compound is also being tested in non-small cell lung cancer. The German company’s phase III IPF trial is not likely to report for another two years, meaning a launch might not take place until 2015.
The phase II pipeline is a little richer since the last time EP Vantage reviewed progress in the disease, with biologicals beginning to take a major place among the candidates. Celgene’s c-Jun N-terminal kinase (JNK) inhibitor CC-930 is the most prominent small molecule – it aims to block overexpression of endothelin-1, which is thought to be a major disease pathway in IPF. A phase II trial could report later this year.
The first antibodies to report may be Johnson & Johnson and MorphoSys’ CNTO-888 and Bristol-Myers Squibb and FibroGen’s FG-3019, both in phase II safety and effectiveness trials. Data at clinicaltrials.gov suggest both could report any day now. The BMS candidate targets connective tissue growth factor.
STX-100 and Novartis’ QAX576 will be the next cohort of antibodies to report, with the Novartis candidate due to show data from a 40 patient study and the Biogen molecule the findings of a 32 patients trial in mid-2013. Novartis’ candidate targets the pro-inflammatory cytokine interleukin-13 and STX-100 blocks the integrin avb6, thought to be involved in the signalling of a growth factor key to development of IPF.
Another biological approach is mondoBiotech’s DasKloster 1001-01, or interferon gamma-1b, using the anti-inflammatory approach that has made that drug class successful in such conditions as rheumatoid arthritis.
Frustration has been the watchword in treatment for IPF, but with such an unmet medical need, it is not surprising that drugmakers are keen to have a try with new approaches. Their progress will be watched closely.