Widely known for its product portfolio of oncology drugs, Revlimid and Pomalyst, Celgene's (NASDAQ:CELG) foray in the inflammation and immunology segment or I&I segment seems to be largely under-appreciated. The company has been exploring three promising oral drugs, Otezla, Ozanimod, and GED-0301, each with different mechanism of action, in inflammatory bowel disease or IBD space. With these research efforts, Celgene has strategized to cement its position in the underserved areas of Crohn's disease and ulcerative colitis.
As clinical trials continue to turn up with positive data, Celgene's planning and timelines for GED-0301 have remained mostly on track. The company has planned to submit new drug application or NDA to the U.S. Food and Drug Administration or FDA for GED-0301 in 2018. GED-0301 is expected to be launched as Crohn's disease therapy in USA in 2019.
This article will focus on GED-0301's clinical profile and discuss data from ongoing and completed clinical trials. This will help in understanding why the investigational drug has potential to transform IBD segment and become a major growth driver for Celgene in future years.
So why is Crohn's disease an attractive growth opportunity?
Aproximately one million patients in USA and European Union have been diagnosed with Crohn's disease. Moreover, one one-third of these patients manage to achieve clinical remission or complete disappearance of disease symptoms, using existing therapies. If we count the number of patients who manage to maintain remission after one year, the performance falls even further. Here only one-fifth of the patients demonstrate sustainable clinical remission numbers. Hence, there is a highly underserved market here for new drugs and especially oral compounds to make their mark. Oral therapies generally lead to better patient compliance due to ease of use, resulting in improved clinical outcomes.
And existing therapies have been unable to meet this demand
Existing therapies in the market for Crohn's disease are also found to be severely lacking, in terms of long-term efficacy, safety, and tolerability. So patients are generally prescribed Entocort (ileal release budesonide) or other corticosteroids as first-line treatment for Crohn's disease. These steroids decrease inflammation, reduce pain and diarrhea. However, they do not cure the Crohn's disease.
Compared to other steroids, budesonide results in lower systemic exposure or impact on other parts of the body. As it works only in the guts, the drug has relatively fewer and mild side-effects such as headache, nausea, heartburn.
It should be noted that all corticosteroids, including budesonide, works by suppressing the immune system. Hence, in worst case scenarios, it may increase the probability of serious opportunitistic infections. Due to their high toxicity, ideally steroids are only suited as initial or induction therapy. However, due to want of better alternatives, patients land up using the drugs for longer term. This increases the possibility of being affected with adverse events related to immune system suppression. Further, patients may also become dependent on steroid usage for getting relief from disease symptoms.
Four tumor necrosis factor or TNF inhibitors, UCB's Cimzia, AbbVie's (NYSE:ABBV) Humira, Johnson & Johnson's (NYSE:JNJ) Remicade and Biogen's (NASDAQ:BIIB) Tysabri, are also approved by the FDA for patients suffering with Crohn's disease. Unlike steroids, these drugs not only provide relief from disease symptoms but may also prove successful to some extent in curing Crohn's disease. However, as TNF inhibitors also suppress the immune system, they also increase the likelihood of patients falling prey to infectious diseases.
As an off-label use, patients are also being prescribed azathiprine and 6-Mercaptopurine as a treatment for Crohn's disease. While efficacy for these drugs has not been clearly demonstrated, their side-effects have been well-documented. These drugs come with black-box warning for its toxicity in terms of increasing chances of skin cancers and non-Hodgekin lymphomas in patients.
So with no safe and effective drugs currently available, Celgene plans to position investigational therapy, GED-0301 as one of the preferred regimens in future years. The drug is expected to become physician's and patient's choice due to anticipated improvements in clinical efficacy and systemic exposure resulting in lesser side-effects as compared to existing standard of care. Further, the therapy is also expected to benefit due to its oral mode of delivery.
Where does GED-0301 fit in the treatment paradigm for Crohn's disease?
Celgene may position GED-0301 mainly in earlier stages of treatment for Crohn's disease, as a prebiologic. This estimation is based on positive results from Phase 2 dose ranging study, which evaluated efficacy of 10mg, 40mg, and 160mg daily dosages of GED-0301, as compared to a placebo, in patients suffering with active Crohn's disease. These results were announced on March 18, 2015, and involved 166 patients afflicted with moderate-to-severe Crohn's disease.
It was seen that 65% of the patients who were administered 160mg daily dosage, demonstrated clinical remission on day 15 and day 28 of the trial. This was in sharp contrast to results seen for patients on placebo as only 10% of these patients achieved clinical remission on these days. 67% patients on 160mg daily dosage of GED-0301 reached gluticocorticoid-free clinical remission on 84th day of the trial.
The phase 2 trial demonstrated efficacy of 40mg and 160mg dosages of GED-0301. This has helped Celgene in zeroing on 160mg daily dosage of the drug, to be tested in Phase 3 trial.
CD-001 trial data further reiterates efficacy of GED-0301
On September 12, 2016, Celgene announced interim top line results from ongoing Phase 1b trial, CD-001, which is studying GED-0301 in patients with active Crohn's disease. The efficacy of the drug in this difficult-to-treat patient population is being used measured based on clinical remission, clinical response, and endoscopic improvements. These 63 patients had also confirmed endoscopic inflammation at the start of the trial.
In CD-001, GED-0301 is being tested on a heterogeneous patient population which comprises of those who failed to respond to TNF inhibitors as well as those who have undergone surgeries. Patients suffering with proximal and distal Crohn's disease were included in the trial. The study has been enrolling patients from multiple countries and has 80% of its trial subjects from North America.
The above diagram shows design of CD-001 trial. This trial involves patients with Crohn's Disease Activity Index score in the range of 220 to 450 and involved either ileum, colon, lower small intestine, or all the parts. These patients also had endoscopically visible disease symptoms, which were measured through using simple endoscopic score for Crohn's disease or SES-CD. Here patients have SES-CD score equal to or higher than 7. For patients with Crohn's disease involving ileum, SES-CD score had to be higher than 4. It was also required that the patients also fail to respond to one of the existing therapies such as budesonide, aminosalicylatyes, immunosuppressants, TNF inhibitors, and corticosteroids.
While the trial has specifically focused on difficult-to-treat patient population, it has excluded those with Crohn's disease restricted to left colon as well as those with Crohn's disease complications such as fistulas, strictures, and abscesses. Patients who had been surgically operated in past six months prior to enrollment or those who had undergone intra-abdominal surgery in past three months before enrollment, were excluded. Finally, patients who failed to respond to more than two TNF inhibitors or therapy with integrin antagonists, were rejected from the trial.
The trial has set its primary objective based on improvement in SES-CD score while secondary objective is based on improvement in CDAI score and safety and tolerability of drug.
So according to interim data obtained from CD-001, use of GED-0301 for 12 weeks in this patient population, has resulted in drop in CDAI score by 133 points from baseline. Also greater than 50% of reduction in CDAI score seems to have happened after first two weeks of therapy. This highlights rapid onset of action of the drug in controlling disease symptoms.
So when clinical response is measured using CDAI score, it was seen that 53% patients on 4 week therapy, 44% on 8 week therapy, and 67% patients on 12-week therapy, managed to demonstrate at least 100 point reduction in CDAI score at end of 12 weeks. Now, doubts can be raised as 8-week therapy has reported lower results than 4-week therapy. Since the sample size in the clinical trial is small, it will not be prudent to pay excessive attention towards the actual numbers recorded. More important is to understand whether the treatment of disease has proceeded in the correct direction. More reliable statistics can be obtained in Phase 3 trial with larger test population.
If we talk about clinical remission based on CDAI scores, 32% patients on 4-week therapy, 35% on 8-week therapy, and 48% on 12-week therapy achieved clinical remission at end of 12 weeks. Now these numbers can be further segregated across various types of disease severity and drug resistance.
So, if we consider endoscopic severity, 43% patients with SES-CD score lesser than or equal to 12 and 30% patients with SES-CD score greater than 12 achieved clinical remission at end of week 12. If we talk about clinical severity, 46% patients with CDAI score lesser than or equal to 300 and 30% patients with CDAI score greater than 300 achieved clinical remission at end of week 12. 50% of patients who were not exposed to TNF inhibitors and 24% of those exposed to TNF inhibitors achieved clinical remission by week 12. Finally, 44% of patients with proximal disease and 31% patients with proximal and distal disease achieved clinical remission at end of week 12.
Shifting to endoscopic response at end of week 12 which is the key objective of this trial, 37% of all patients demonstrated reduction in SES-CD score by more than 25%. If we consider only those patients with SES-CD score greater than 12 at baseline, similar endoscopic response was demonstrated by 63% of the patients. 15% of all patients and 31% of patients with SES-CD score greater than 12 at baseline demonstrated greater than 50% reduction in SES-CD score, at end of week 12 of the trial. Two of the 63 patients had complete endoscopic remission at end of week 12. 43% of TNF naïve patients and 29% of TNF exposed patients demonstrated reduction in SES-CD score by more than 25% at end of 12 weeks. Also, 32% of patients with proximal disease and 42% with both proximal and distal disease demonstrated drop in SES-CD by more than 25%.
Biomarkers such as fecal calprotectin and C-reactive protein, present in stool as a marker of inflammation, have also highlighted efficacy of GED-0301.
So what does the data boil down to?
Based on overall trial results, there is definite preference for 12 week dosing regimen of GED-0301 at earlier stages of Crohn's disease. Besides efficacy, there have been no significant adverse events associated with the drug. As systemic exposure of the drug is seen to be negligible, it makes a case for strong benefit-risk profile for the drug. Hence, strong clinical profile of GED-0301 compares favorably in stark contrast to existing Crohn's disease therapies.
Celgene can thus position GED-0301 as a leading drug in the IBD market. Hence, it will be wise for a long term biotechnology investor to keep a close eye on GED-0301 research programs while considering Celgene as an investment opportunity.
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