The doors to Boehringer Ingelheim’s research labs might not be quite as securely bolted as they used to be, but the German pharma giant is still relatively tight-lipped about its activities. As a private company it is under no obligation to reveal anything about its R&D work, of course, but with an annual budget of almost €3bn ($3.6bn), where its money is going is of interest.
At its first R&D day in two and a half years last week, Boehringer highlighted its efforts in immuno-oncology – a Smac mimetic received particular attention – while it promised to shortly release the first data on what it claims is a first-in-class IL-36 receptor inhibitor, under investigation for a rare form of psoriasis. The company also unveiled a strong interest in neuroscience – a field more notable for the exit of big pharma names (see pipeline below).
Its lead candidate here is a PDE-9 inhibitor, which it is pushing forward in schizophrenia. The theory is that inhibiting the PDE-9 enzyme enhances brain plasticity – BI 409306 strengthens glutamate receptor signalling by boosting post-synaptic cGMP, an important signalling molecule.
Boehringer is not alone in this space, though it appears to have the most advanced asset – Eisai has an earlier-stage PDE-9. Phase II data on BI 409306 remain a couple of years away, according to clinical trial entries. Two studies have been designed to answer some atypical questions: the first looks at whether BI 409306 can delay the onset of schizophrenia and the second explores whether it can prevent relapses.
Boehringer says these designs reflect its attempts to address psychiatric conditions via “symptom domains”. These transcend traditional disease classifications, which frequently do not reflect underlying mechanisms, the company believes. So its TRPC4/5 inhibitor, for example, targets brain circuits involved in anhedonia – the inability to experience pleasure – and a loss of interest in activities, which can be a symptom of many mental health disorders.
|A glimpse through the door - projects highlighted at Boehringer's 2018 R&D day and other selected assets|
|Central nervous system|
|BI 409306||PDE 9 inhibitor||Two large phase II trials ongoing schizophrenia||NCT03230097; NCT03351244|
|BI 425809||GlyT1 inhibitor||Two large phase II trials ongoing in AD and schizophrenia||NCT02788513; NCT02832037|
|BI 1358894 (from Hydra)||TRPC4 & 5 blocker||Phase I started in late 2017 in healthy volunteers||NCT03210272|
|AUT00206 (from Autifony)||Kv3 potassium channel modulator||Phase I ongoing in schizophrenia; BI has option||NCT03164876|
|Risankizumab (Abbvie has WW rights)||Anti-IL-23 MAb||Filed in the US in psoriasis; PIII trials in Crohn's and ulcerative colitis ongoing||NCT03105128; NCT03398148|
|BI 655130||Anti-IL-36 receptor MAb||Data in GPP to be published shortly, PII/III in ulcerative colitis ongoing||NCT02978690; NCT03482635|
|BI 655064 (Abbvie has option)||Anti-CD40 MAb||Two phase II lupus trials ongoing||NCT02770170; NCT03385564|
|Ofev||Multi-TKI||PIII trials in systemic sclerosis and PF-ILD at advanced stage||NCT03313180; NCT02999178|
|BI 1467335 (from Pharmaxis)||AOC3 inhibitor||Phase II trials in NASH and diabetic retinopathy ongoing||NCT03166735; NCT03238963|
|BI 836845 (xentuzumab)||IGF 1 & 2 MAb||PI trials in breast cancer ongoing, incl. combo trials with Eli Lilly's abemaciclib||NCT03099174; NCT02123823|
|BI 836858||Anti-CD33 MAb||PII trials ongoing in MDS and AML||NCT02240706; NCT02632721|
|BI 1361849/CV9202 (from Curevac)||mRNA cancer vaccine||Combination trial with Imfinzi and tremelimumab ongoing||NCT03164772|
|BI 836880 (from Ablynx)||ANG 2 & VEGF bispecific nanobody||PI trials ongoing in solid tumours||NCT02674152; NCT02689505|
|BI 754091||Anti-PD-1 MAb||PI mono and combination trials on-going||NCT02952248|
|BI 754111||Anti-LAG 3 MAb||PI combo trial with anti-PD-1 antibody||NCT03156114|
|BI 891065||SMAC mimetic||PI combo trial with anti-PD-1 antibody||NCT03166631|
|BI 894999||BET bromodomain inhibitor||PI trial ongoing in advanced malignancies||NCT02516553|
|Source: EvaluatePharma, company presentation, clinicaltrials.gov. Note: excludes respiratory disease area, which is not covered in depth in this article. GPP: generalised pustular psoriasis, PF-ILD: progressive fibrosing interstitial lung disease.|
Also in mid-stage development is an IL-36 receptor inhibitor, BI 655130. Boehringer has released nothing on the product so far, although the signs are presumably encouraging as last month it started a 550-patient phase II/III trial in ulcerative colitis. At the presentation the company highlighted the project's effectiveness in generalised pustular psoriasis (GPP), a very rare and severe form of the condition in which various genetic mutations, including in a gene called IL36RN, have been implicated.
Data in GPP are likely to be published very soon, Dr Michel Pairet, head of BI’s Innovation Unit, told EP Vantage, adding that the data are convincing enough to justify wider research. “Incidence of GPP is very low – maybe 20,000 to 30,000 patients – so this will not be the business case. We see potential in other indications – ulcerative colitis, Crohn’s, palmoplantar pustulosis,” he said.
Again, Boehringer is not alone here – Anaptysbio has an anti-IL36 compound, ANB019, that it plans to push into phase II in GPP and palmoplantar pustulosis this year.
Elsewhere in the pipeline, work in fibrotic disease was highlighted, in the lung and the liver. Like many others the company believes Nash is a big future disease area and proof of principle data should emerge from its Pharmaxis-partnered project in 2019.
Much attention at the R&D day was given to cancer, an area where Boehringer has invested fairly heavily but has yet to make much of a splash – its most notable product is probably the kinse inhibitor Gilotrif for lung cancer.
Targeted therapies like this remain a focus, Mr Pairet said, although work is early stage – within the next 12-18 months agents targeting KRAS and the WNT pathway should enter the clinic.
Boehringer’s work in immuno-oncology is only slightly more advanced, with just a couple of projects in the clinic. One to watch will be its Smac mimetic, BI 891065, which Boehringer says elicited dramatic effects in an aggressive tumour model when combined with anti-PD-1 blockade.
Smac – or second mitochondria-derived activator of caspase – is an endogenous protein that blocks inhibitor of apoptosis (IAP) proteins. These IAPs promote cancer cell survival and proliferation, while mutations in IAP genes are also associated with various tumour types.
Notably, Boehringer seems to have already ruled out a monotherapy approach with BI 891065. Mr Pairet said that by priming the immune system as well as upregulating cell death signals, these agents could turn cold tumours hot, and boost the effectiveness of checkpoint blockade.
“This is why we are working on these immunogenic cell death inducers – one example is the Smac mimetic, which in our mind is one of the best mechanisms to induce this,” he said.
Other immunogenic cell death inducers in Boehringer’s pipeline include cancer vaccines, oncolytic viruses and dual antibodies for T-cell engagement, all of which Mr Pairet believes hold potential to prime less immunogenic tumours.
Boehringer told EP Vantage that it focused its strategy around three years ago to solid tumours that are poorly infiltrated by the immune system, which prompted it to search for agents directed to early immune activation processes.
Only the Smac mimetic and an mRNA cancer vaccine from a Curevac partnership, CV9202, have made it into combination trials so far. Data are unlikely to emerge on either this year, Mr Pairet indicated, though within the next 12 months one of Boehringer’s oncolytic virus projects should enter the clinic. He agreed that the track record of many of these agents is not great, but expressed confidence that their potential could be found via combination strategies.
Boehringer might be playing catch-up in immuno-oncology, but its strategy does at least seem to take on board a finding made by some of its peers after incurring significantly more expense: that combining two checkpoint mechanisms has little additive effect. And its efforts here are serious – a third of the company’s projects due to reach the clinic next year are in oncology, Mr Pairet said.
Mr Pairet also indicated that the company’s preference for early-stage deal making is unlikely to change, stating that Boehringer likes to get into an area and build a strong position before it becomes crowded.
“We rely on our good nose to pick the right asset when not everyone is aware of them,” he said, adding that late-stage investments have not been completely ruled out.
Of course making very early bets is a luxury that a private company can afford more easily, away from the very public pressures of quarterly reporting and demanding short-term investors. At this moment in time Boehringer clearly feels no need to change this radically, or provide its competitors with more granular information on mechanisms, timelines and strategies.
No doubt many executives at Boehringer’s public peers view this stance with some envy.