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Global Blood Therapeutics: STAT Article Sparks Worry, But Much Of It Is UnwarrantedGlobal Blood Therapeutics: STAT Article Sparks Worry, But Much Of It Is Unwarranted Sep. 17, 2018 8:21 PM ET|15 comments | About: Global Blood Therapeutics (GBT) Clover Biotech Research / SA Sept 17, 2018 https://seekingalpha.com/article/4206802-global-blood-therapeutics-stat-article-sparks-worry-much-unwarranted Summary Adam Feuerstein of STAT news released an article last week that was likely responsible for an 8% dip in shares of Global Blood Therapeutics. Titled "Global Blood’s FDA filing plan for a sickle cell drug is riskier than you think," the article raises many doubts surrounding Voxelotor's regulatory prospects. In the following article, I address four main points raised in the STAT article. This idea was discussed in more depth with members of my private investing community, The Formula. Get started today » A STAT article released last Thursday was met with immediate selling in Global Blood Therapeutics (GBT), as shares took a considerable dip on above-average volume: The article's debut happened to coincide with The Sickle Cell Therapeutics Conference, which Ted Love (CEO of Global Blood Therapeutics) hosted and participated in. Let's take a closer look at some of the points Feuerstein made in the article and address them head-on: Four Misconceived Points (Note: The four points below are paraphrased from the article.) - The results for Phase 3 were "mixed". - The FDA has "traditionally" required data demonstrating a sickle cell disease drug under review is able to significantly reduce pain events. - There is no evidence that Voxelotor reduces pain events. The data released in June "failed" to demonstrate reductions in pain events. - Senicapoc also increased hemoglobin and reduced hemolysis, but didn't decease pain events. Phase 3 Part A Results Were Not "Mixed" The results were only "mixed" for those who did not understand the trial design. I've written about the misconceptions surrounding Phase 3a data. Read here. To summarize: Part A was never designed to determine statistical significance in secondary endpoints (vasoocclusive crises and Patient-Reported Outcomes). Part A was always designed to: (1) finalize the dose and (2) finalize the secondary endpoints. The secondary outcomes GBT reported in Part A were neither "negative" nor the fault of the drug. The Scientific Community Is Making Strides Towards Non-Traditional Endpoints For Sickle Cell Disease Yes, traditionally the FDA has required VOC as a primary endpoint for a sickle cell disease drug. Granted, voxelotor, although it has shown promise in reducing VOC, has not statistically proven (p<0.05) a significant ability to reduce VOC. Despite this, it has earned: Breakthrough Designation Therapy (first and only SCD drug to do so), Fast Track Designation, Orphan Drug Designation, and PRIME designation. This is because science recognizes the need for therapeutics that address other aspects of sickle cell disease beyond pain. Additionally, the FDA and GBT agreed on the primary endpoint - that raising hemoglobin by 1 g/dL was a valid primary endpoint because increasing hemoglobin in these patients by that amount is associated with improved clinical outcomes (stroke, mortality, organ failure, etc.). Finally, the scientific community is aware of the need for new (nontraditional) endpoints for sickle cell disease trials. The American Society of Hematology recently announced a workshop that may be pertinent to Global Blood Therapeutics' prospects: For regulatory approval of therapeutics for the treatment of SCD, the FDA requires clinical endpoints that show direct evidence of clinical benefit or improvement in an established surrogate for clinical benefit. Since the original hydroxyurea approval, science and technology have evolved, and medical care delivery for patients with sickle cell disease has changed. The robust SCD drug development pipeline is poised to deliver new therapies to patients; however, there is general agreement that a timely discussion about endpoints is needed. To facilitate this discussion, the FDA and ASH are convening this public workshop focused on clinical endpoints for SCD. The discussion and recommendations from the workshop will be published and shared with the SCD community. The workshop will include seven panels on the following topics: - Patient reported outcomes - Pain (non-PRO) - Brain - End organ considerations, such as cardio-pulmonary and renal - Biomarkers - Endpoints related to curative therapies, including bone marrow transplantation, gene therapy, gene editing, and gene switching - Considerations of endpoints for low-resource settings Global Blood Therapeutics believes some of the following scientific findings will support its proposed surrogate endpoint (hemoglobin) in achieving accelerated approval: - Association of lower hemoglobin and stroke - here - Association of low hemoglobin and silent cerebral infarct - here - Impact of increasing hemoglobin (via transfusion) on reducing stroke - here - Low hemoglobin and higher risk for death - here - Hydroxyurea therapy lowers transcranial doppler flow velocities in children with sickle cell anemia - here - Prevention of conversion to abnormal transcranial doppler with hydroxyurea in sickle cell anemia: A phase III international randomized clinical trial - here There Is Data Supporting Voxelotor's Ability To Reduce Vasoocclusive Crises This point lacks understanding into the data and the trial design. There is data that demonstrates Voxelotor reduces VOC ("numerical reductions" in a phase 3 trial, see compassionate use study). Therefore, this statement is false. Perhaps, he meant to say Voxelotor lacks "statistically significant" data? Besides that, Phase 3a wasn't powered to reveal statistically significant differences in VOC (limited follow-up), nor is 12 weeks probably a long enough period to demonstrate that Voxelotor decreases VOC in patients with relatively well-controlled SCD. These enrolled patients, in general, have only two or three VOCs per year. Therefore, they may average a VOC episode every 18-26 weeks. (Part A of the trial was only 12 weeks.) L-glutamine (Endari) secured accelerated approval in 2017, based on a randomized, double-blind, placebo-controlled trial that enrolled 230 patients. To sum up the results: Over the 48-week period, patients receiving L-glutamine had a median of 3 sickle cell crises compared with a median of 4 crises for those receiving placebo. Treatment with L-glutamine also resulted in fewer hospitalizations due to sickle cell pain, fewer cumulative hospital days, and a lower incidence of acute chest syndrome. The image below represents the separation of L-glutamine and placebo in mean cumulative number of pain crises. Notice, the treatment and placebo begin to really differentiate around week 24. Source: New England Journal of Medicine It also is important to consider that the patients in this trial have more VOC events per year than patients in Global Blood Therapeutics' trial. Therefore, it is certainly an easier task for L-glutamine to quickly demonstrate an ability to reduce VOC than it is for Voxelotor. Comparing Voxelotor With Senicapoc Is Not A Fair Argument Within the article, Feuerstein cites a recycled argument that is made against Voxelotor: there was another drug that also improved hemolytic anemia but did not result in clinical benefits (e.g., reduction in pain events). Perhaps, cleverly not recycled by Feuerstein, senicapoc was actually shown to significantly increase vasoocclusive crises compared to placebo: Interestingly, despite its clear effect on reducing haemolysis, the drug paradoxically increased the rate of pain episodes. In fact, when the analysis of crisis rate was limited to patients with Hb SS (n = 245), the crisis rate among patients randomized to senicapoc was significantly higher than that in patients randomized to placebo (0·41 vs. 0·30 events per 52‐week treatment period, P = 0·004). This represents a 36% increase in pain episode incidence among Hb SS subjects. Additionally, senicapoc wasn't as effective as Voxelotor with improving hemolytic measures. In fact, if senicapoc were to go through the same trial design as Voxelotor, it wouldn't meet the primary endpoint: Notable conversion: 1 g/L = 0.1 g/dL; 1 g/dL = 10 g/L As of late, folks have enjoyed comparing senicapoc with Voxelotor as a way to dismiss the efficacy of Voxelotor. However, it is neither a fair nor relevant argument. Summary I'm not going to say Global Blood Therapeutics will achieve accelerated approval. I do not know. I do, however, believe it is likely. My investment thesis in GBT does not rely on how Voxelotor makes it to the market. Rather, I continue to believe that Voxelotor, especially because it improves hemolytic anemia associated with disease without increasing pain events (at the least), demonstrates disease-modifying capabilities and will become standard-of-care for sickle cell disease patients regardless of its destined path into the market (via accelerated approval or not). I believe GBT trading in the low $40s/share presents us with an opportunity to accumulate shares at a cost-advantageous manner. Author's note: For further research and insight into other biotech conviction ideas, subscribe to The Formula today! Disclaimer: The intention of this article is to provide insight, not investment advice. While the information provided in this article is intended to be factual, there is no guarantee and prospect investors are encouraged to do their own fact-checking and research before investing in a company. One must also consider one's own financial standings, risk tolerance, portfolio diversification, etc. before making a decision to buy shares in a company. Many of my articles detail biotechnology companies with little or no revenue. These stocks are, therefore, speculative and volatile. Even when prospects seem promising, there is no predicting the future. Losses incurred may be significant. Disclosure: I am/we are long GBT. |
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