Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts tagged ‘Landscape’

In today’s post we answer some reader mailbag questions pertaining to targeting BET/bromodomain inhibitors and what we’ve learned since our original landscape review from early 2016 when they were an emerging new class in the oncology R&D space – how time flies!

Is it time-up for the bromodomain class?

Of course, as usually happens in the targeted therapy space we see a glut of pan inhibitors trying to block everything in sight to a greater or lesser degree… we’ve see this with BRAF, FGFR, PI3K, and even KRAS inhibitors, as well as numerous others, yet these rarely turn out to be the bees knees we’re secretly looking for. Bromodomains, I have long argued, were ripe to fall in this category as well.

Instead, it is better to patiently wait for the next generation molecules where they are much more selective in their actions and matched to the tumour target we are looking to hit.

Think about the BRAFV600E vs. pan BRAF inhibitors or KRASG12C/D vs. pan KRAS inhibitors, for example, or even FGFR2 or FGFR3 vs. pan FGFR inhibitors.

The same evolution may possibly happen in the BET/bromodomain space too.

The first generation of agents seemed to hit everything – BRD1, 2, 3, 4, and often BET as well. They suffered, however, with weak efficacy largely driven by challenges with the on-target, off-tumour effects that necessarily impact the therapeutic window.

Now we are starting to learn from a more focused approach with these agents. Four years on from our original landscape review, what’s hot and what’s not? Who’s in and who’s out? In terms of the magic roundabout of oncology R&D, are there any new gems we should eagerly be watching out for?

The short answer is yes… but what are they and who owns them?

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A path through the CD47 wilderness?

Continuing the third part of our ongoing CD47-SIRPα mini-series, we move on from the science and the competitive landscape to look at what CEOs in this niche have to say. There are many different approaches being evaluated at present, mostly in preclinical development, which makes it an intriguing area to potentially follow over time as new data emerges.

Not all of these molecules will be successful and the target is certainly not the easiest to attempt, although not as diffcult as MYC or RAS either!

When all is said an done, what do key players in this field think when they are developing compounds and how do they see the emerging challenges?

In this latest post, we have not one, but two CEOs, who were willing who share their candid thoughts and perceptions on the CD47-SIRPα space…

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Choose your clinical gateway!

When an oncology R&D landscape starts getting crowded and highly competitive, how do you go about working out clinically meaningful differences between compounds in development?

After all, there are often a myriad of small differences and nuances in the preclinical approach that may or may not be useful when it comes to the clinic.

Sometimes design matters, whether this be in the way the molecules are built or function, perhaps in tumour types that are selected for study, while at other times trial design can impact outcome.  In short, much like a 3D chess game it can get complicated pretty fast.

One such area that has been receiving increased attention lately and also has a lot of complexity to consider is the CD47-SIRPα pathway.

Last week we covered some of the key basics in a primer exploring the science in Part 1 of this mini-series.

Tomorrow we will post Part 3, which focuses on candid comments from researchers and CEOs in this niche, but before we get there it’s time to look at key clinical perspectives, as well as some of the nuances from related pathways that may be important factors to consider.

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Inspire Pharmaceuticals (NASDAQ:ISPH), a North Carolina based biopharmaceutical company that focuses on products for ophthalmic and pulmonary diseases, recently announced positive results from their phase 3 trial (TIGER-1) of denufosol tetrasodium in patients with Cystic Fibrosis (CF).

Cystic Fibrosis is a genetic disorder that can lead to death as a result of pulmonary complications from airway obstruction, bronchial thickening and accumulation of mucous.  Lung function tests are widely used in the diagnosis, treatment and management of patients with CF.  Measurement of FEV1 (Forced Expiratory Volume in 1 second) is regarded as the best predicator of mortality.  As the disease progresses and the lungs become more obstructed, FEV1 decreases.

Inspire Pharma’s denufosol is an ion-channel regulator that helps keep the airways moist and helps mucous removal in CF patients.  It increases chloride secretion via calcium-activated chloride  channels (CaCCs), inhibits sodium absorption via epithelial sodium channels (ENaCs) and stimulates ciliary beat frequency.  Conveniently for patients, it is being developed as an inhaled drug delivered direct to the lungs by nebulizer.

The phase 3 clinical trial data presented by Dr Frank Accurso at the Annual North American Cystic Fibrosis Conference, and in the paper published in the American Journal of Respiratory and Critical Care Medicine (AJRCCM), showed an improvement in lung function after 24 weeks in patients with mild CF who received daily denusofol by means of a nebulizer.  The primary efficacy endpoint was a change in FEV1:

Source: October 21, 2010 presentation by Frank J. Accurso M.D. to North American Cystic Fibrosis Conference.  Available at Inspire Pharma.

Dr Accurso and his colleagues reported that the results demonstrated:

“Mean change from baseline to Week 24 endpoint in expiratory volume at 1 second (primary efficacy endpoint) was 0.048 L for denufosol (n=178) and 0.003 L for placebo (n=174; P=0.047).”

Despite the significant improvement in FEV1, there was no significant difference between the denufosol and placebo arms in the time to progression to first pulmonary exacerbation, suggesting that its long-term clinical effectiveness remains uncertain.

Source: October 21, 2010 presentation by Frank J. Accurso M.D. to North American Cystic Fibrosis Conference.  Available at Inspire Pharma.

Notwithstanding, these results do offer hope to patients with mild symptoms of Cystic Fibrosis.  Early treatment to maintain lung function may delay the onset of more severe physiological changes and the need for more radical treatment options such as a heart/lung transplant.

Thanks to BBC Health for writing about this topic and giving me the idea for this post.

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