StemCell Therapy

Global Blood Therapeutics, Inc. (GBT) confirmed that the FDA has approved Oxbryta (voxelotor) tablets for the treatment of sickle cell disease in adults and children 12 years of age and older. According to the company press release, Oxbryta is the "first and only FDA-approved sickle hemoglobin polymerization inhibitor, a new class of therapy."

Earlier, the company presented updates on corporate developments on 10/8/2019 at its Analyst & Investor Day. Global Blood is a clinical-stage biopharmaceutical company having expertise in blood biology and structural and medicinal chemistry. The company's lead product candidate is voxelotor ('GBT440), an oral, once-daily therapy, designed to modulate hemoglobin affinity for oxygen for the treatment of sickle cell disease (SCD). SCD is an inherited blood disorder caused by a genetic mutation in the beta-chain of hemoglobin, leading to the formation of abnormal hemoglobin known as sickle hemoglobin (HbS).

HbS polymerizes forming rigid rods within a red blood cell (RBC). The inflexible polymer rods arranged in a sickle shape, cause hemolytic anemia (destruction of RBCs) that can result in multi-organ damage and even early death. This sickling process blocks capillaries and small blood vessels. Blocked bloodflow to organs results in inadequate oxygen delivery (hypoxia) to body tissues, which makes the SCD patients suffer recurrent and unpredictable episodes of severe pain, ultimately leading to physical and psychosocial disabilities. Voxelotor is designed to inhibit HbS polymerization.

Voxelotor had been granted priority review for the treatment of SCD, with PDUFA date set to February 26, 2020. Priority review shortens the FDA review time from the standard 10 Months to 6 months. The accelerated approval 3 months ahead of PDUFA speaks for the importance of this novel drug in the eyes of the FDA.

The NDA was based on data from the multi-national Phase 3 HOPE study, which demonstrated statistically significant and sustained improvements in hemoglobin with voxelotor. Looking at the critical need for new SCD treatments, the U.S. FDA earlier granted Breakthrough Therapy, Fast Track, Orphan Drug and Rare Pediatric Disease designations to voxelotor for the treatment of patients with SCD. The European Medicines Agency (EMA) has also included voxelotor in its Priority Medicines (PRIME) program, while the European Commission (EC) has designated voxelotor as an orphan medicinal product for the treatment of patients with SCD.

Design: The efficacy and safety of two dose levels of voxelotor, 1500 mg and 900 mg, administered orally once daily, was compared with placebo in persons with SCD in a multicenter, Phase 3, double-blind, randomized, placebo-controlled trial "HOPE." The percentage of participants who had a hemoglobin response, defined as an increase of more than 1.0 g per deciliter from baseline at week 24 in the intention-to-treat analysis was the primary endpoint. 274 participants in total were randomly assigned in a 1:1:1 ratio to receive a once-daily oral dose of 1500 mg of voxelotor, 900 mg of voxelotor, or placebo. Most participants had sickle cell anemia (homozygous hemoglobin S or hemoglobin S0-thalassemia), and approximately two thirds were receiving hydroxyurea at baseline.

Results: The Phase 3 study met the primary endpoint with nearly 60% of patients achieving >1 g/dL increase in Hb vs. placebo (p<0.001). A significantly higher percentage of participants had a Hb response in the 1500-mg voxelotor group (51%; 95% confidence interval [CI], 41 to 61) than in the placebo group (7%; 95% CI, 1 to 12), in the intention-to-treat analysis. Anemia worsened between baseline and week 24 in more placebo-treated participants than in each voxelotor dose group.

At week 24, the 1500-mg voxelotor group had significantly greater reductions from baseline in the indirect bilirubin level and percentage of reticulocytes than the placebo group. Adverse events (AEs) of grade 3 or above occurred in 26%, 23% and 26%, in the 1500-mg voxelotor group, the 900-mg voxelotor group, and the placebo group respectively. Most AEs were not treatment emergent either with the trial drug or placebo. Voxelotor increased hemoglobin levels and reduced markers of hemolysis significantly. The results are consistent with inhibition of HbS polymerization.

(Image source: Company presentation)

The company in agreement with the U.S. FDA, has already designed the post approval, confirmatory study of voxelotor, utilizing TCD flow velocity as the primary endpoint.

There are millions of SCD patients worldwide with 90,000 to 100,000 in the U.S. and about 60,000 in Europe. SCD is a congenital disease, with symptoms and organ damage starting in the early years of life. It is estimated that worldwide 250,000 to 300,000 children are born annually with SCD, which is concentrated in populations of African, Middle Eastern and South Asian descent. SCD treatment is costly, with average annual cost in the U.S. being more than $200,000 for an adult, which can lead to aggregate expense of more than $8 million over an assumed 50-year lifespan. Newborn screening, which is required by all states in the U.S., and development of new therapeutics is hence a critical need of the market.

GBT raised approximately $197.8 million in net proceeds from a public offering in June 2019 and related over-allotment option exercise in July 2019. GBT had cash, cash equivalents and marketable securities totaling to $731.7 million as of 6/30/2019. Looking at the cash burn of about $61 million in the most recent quarter ending 6/30/2019, GBT's fund position seems to be at an adequate level to carry through the commercialization of voxelotor, and other development activities without further dilution of the stock. Insiders sold a negligible, less than 15000 shares in the last 52 weeks. Institutional holding increased over 2% in 2Q-2019.

The company awarded more than $200,000 in grants to five nonprofit organizations as part of the Access to Excellent Care for Sickle Cell Patients Pilot Program (ACCEL). The grant funding will support projects to improve access to high-quality healthcare for SCD patients in the U.S. The company has launched two SCD awareness campaigns while also hiring all commercial leads as of 1H-2019.

Voxelotor does not have a direct competition as it is attacking the root cause of SCD with a new first-in-class therapy. It faces indirect competition from (1) Bristol-Myers Squibb's (BMY) hydroxyurea (DROXIA or Hydrea) and its generic form, which are approved for "reducing the frequency of painful crises and need for blood transfusions in patients with sickle cell anemia for the treatment of adults with SCD," and (2) Endari (L-glutamine oral powder), marketed by Emmaus (OTCQB: EMMA), approved for the reduction of acute complications in SCD patients of age five years and above. GBT will also face competition from one-time therapies for patients with severe SCD, like hematopoietic stem cell transplantation, gene therapy and gene editing.

bluebird bio, Inc. (BLUE) has a gene therapy candidate in clinical development - LentiGlobin BB305, which the company plans to pursue on an accelerated development path. Pfizers (PFE) rivipansel is in a Phase 3 trial however it failed the treatment goals. Novartis (NVS) crizanlizumab (SEG101), an anti-P-selectin monoclonal antibody for the prevention of vaso-occlusive crises (VOCs) in patients with SCD is in clinical development with a breakthrough designation. The U.S. FDA has accepted for a priority review of crizanlizumab based on its Phase 2 SUSTAIN study results. Estimated PDUFA date is 1/15/2020. GBT also has an anti-P-selectin monoclonal antibody therapy inclacumab, in clinical development, under worldwide, exclusive but non-diagnostic license from Roche (OTCQX:RHHBY).

Various patents covering voxelotor, including its composition of matter, methods of use and a polymorph of voxelotor will expire between 2032 and 2035. Patents that may issue from GBTs pending patent applications relating to voxelotor in the United States or from corresponding foreign patent applications, if issued, are expected to expire between 2032 and 2037. Some patents related to voxelotor are held jointly with the Regents of the University of California.

GBTs other risk is competition. For a long time, Lentiglobin has been talked about as a major competition, and while it is aimed as a curative treatment, it is expensive, and still in a much earlier stage, with the Phase 2/3 trial in planning stage only. Crizanlizumab is also not a real competition either, because it is a downstream therapeutic approach compared to GBTs.

The stock price was near the midpoint of the 52-week high and low before the approval. The approval has pushed the price up by about 20% in the time since the original version of this article was written. However, I strongly believe there's considerably more upside to this stock as the drug gets to the market in the next couple of weeks and starts generating revenue.

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Disclosure: I/we have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

Read more here:
Global Blood Therapeutics: Oxbryta Is Finally Approved - Seeking Alpha

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