Global Blood Therapeutics Inc.

Global Blood Therapeutic Inc.'s homegrown lead candidate is an oral, once-daily drug aimed at sickle cell disease, a genetic condition that causes red blood cells to become deformed or “sickled." The goal with GBT440 is to correct the disease, so that patients would actually have no evidence of it following treatment.

Global Blood Therapeutics Inc.

400 East Jamie Court, Suite 101

South San Francisco, CA 94080

Phone: [phone]

Web Site: www.globalbloodtx.com

Contact: Ted W. Love, MD, CEO

Industry Segment: Biotechnology

Business: Prophylactic treatment for sickle cell disease

Founded: June 2012

Founders & Advisors: Charles Homcy, MD (Third Rock); Craig Muir (Third Rock); David Phillips, PhD; Matthew Jacobson, PhD (University of California, San Francisco [UCSF]); Andrej Sali, PhD (UCSF); Jack Taunton, PhD (UCSF)

Employees: 38

Financing To Date: $98 million

Investors: Third Rock; Wellington Management Co.; RA Capital; Deerfield Management; Sabby Capital; Perceptive Life Sciences; Cowen Group affiliate; Undisclosed public investment fund

Board Of Directors: Willie L. Brown Jr.; Ted Love; Charles Homcy; Kevin Starr (Third Rock); Deval L. Patrick, Mark L. Perry (formerly Gilead Sciences)

For Ted Love, one of a small number of African American biopharma CEOs in the US, work nowadays is also very personal. Love, whose last position was as a senior R&D exec at Onyx, has been CEO at South San Francisco-based Global Blood Therapeutics Inc. (GBT) since mid-2014.

GBT was founded in 2012 by execs at Third Rock Ventures, who launched it with $40.7 million. [See Deal] The start-up raised a $48 million Series B round this past January. [See Deal] The company’s homegrown lead candidate, GBT440, is an oral, once-daily drug for chronic use aimed at sickle cell disease, a genetic condition that causes red blood cells to become deformed or “sickled.” GBT440 will also be developed in other indications where the mechanism makes sense.

Between 90,000 and 100,000 people in the US, the vast majority of whom are African American, have the disease, which can cause stroke, organ damage, infection, and pulmonary conditions, not to mention severe pain. It is treated with addicting painkillers. About half of patients are under the age of 18 and life expectancy in the US is typically in the 40s.

Sickle cell disease traditionally has been neglected – only one drug is approved and it’s a very old one called Droxia (hydroxurea). Originally marketed by Bristol-Myers Squibb Co. as a chemotherapeutic, the drug tacked on an indication in 1998 for sickle cell disease. Hydroxurea carries a risk for secondary malignancies and, according to Global Blood, it is used by only a minority of sickle cell patients. A range of other treatments are employed to manage complications, including regular blood transfusions, antibiotics, and pain medications. Some patients may also be eligible for bone marrow transplants.

Nobody in Love’s family has sickle cell disease, but the exec felt a strong calling to lead the company in light of the potential for a solution to a crippling disease for the African American community. “As an African American in the pharmaceutical industry, what better job than to solve this problem for a community that’s kind of been ignored,” says Love.

Recruited by GBT founders Charles Homcy and David Phillips, Brian Metcalf, PhD, was the key chemist behind the GBT440 invention. Global Blood isn’t releasing details on its patents, but it says that it has “executed a very aggressive intellectual property strategy.”

Global Blood’s candidate works on hemoglobin, a protein in red blood cells that has a dual role of picking up oxygen in the lung, and delivering it to tissues. To perform two opposite functions, it needs to change shape. But in patients with sickle cell disease, due to a genetic mutation, the loss of oxygen causes red blood cells to become deformed into a sickled, or crescent shape. The sickled cells then stick and clump together, blocking blood vessels and causing “vasoocclusive crises,” which can be very damaging and painful. GBT440 binds to hemoglobin and prevents it from fully unloading oxygen, which in theory prevents the transformation into the sickled shape. The goal with GBT440 is not merely to treat crises, but to correct the disease, so that patients would actually have no evidence of sickle cell disease following treatment.

The drug has been on a fast development track, having gone from molecular modeling to IND stage in less than three years. GBT started a Phase I/II trial at the end of 2014 and plans to have proof-of-concept data by the second half of 2015. This could provide enough validation to support the launch of a pivotal trial, which in turn could pave the way for accelerated approval as early as 2018. Given the unmet need, that's a possibility according to Love. “The burden is on us to convince them we have something that we think is of great potential benefit and that has a very attractive safety/efficacy profile. I think if we can do that, the FDA will want to work with us to get this drug approved as quickly as possible,” he says.

The Phase I/II trial, which is being run by Quintiles Inc. at Guy’s Hospital in London, is recruiting up to 128 adults, up to 40 of whom will be patients and the rest healthy volunteers. Proof-of-concept in that study would open a number of different doors for financing, including a public offering or a partnership, Love says. Given the size of the patient population and the narrow indication, the company may opt to commercialize the drug on its own.

Love declines to comment on the total cost of development.

In addition to neglect in terms of drug development, the disease has been burdened with a lot of stigma. Now an industry veteran with over 20 years in the business, Love recalls that when he was a medical student in the early 1980s, care was “terrible.” Treatment often revolved around fixes for pain, which fuelled addiction. “Guess who had made them addicts? We had. None of these people were born with the desire to become addicts. They started getting these drugs because they had sickle cell crisis,” Love says. “It was embarrassing to be part of a system that was providing such poor care to people,” he adds.

At such an early stage of development, the company is currently focusing on adults, with the goal of preventing additional damage from the disease, but Global Blood has a broader vision for development that would include pediatric patients. One day, it’s possible that the drug could be given to babies, preventing sickle cell disease, Love says. “We’d like to have a drug sufficiently safe and effective so you can give it to these children before they ever sickle – never give them Percocet and never give them morphine. Don’t make them addicts and don’t let them have strokes. Don’t let any of that vicious cycle begin – stop it before it starts,” Love says.

While treatment options today are limited, there are encouraging signs of a better future. The Sickle Cell Disease Association of America has hailed provisions of the Accountable Care Act, such as coverage regardless of pre-existing conditions, better preventive care, and longer-term inclusion of children on their parents’ insurance until early adulthood.

The pipeline is also encouraging. In recent years, Big Pharma has taken a real interest in sickle cell disease – Pfizer Inc., Novartis AG, and Baxter AG are among those active in the space today. (See (Also see "Sickle Cell Disease Orphan Status Lures Pharma Interest" - Pink Sheet, 9 Sep, 2013.).) About a dozen drugs are in clinical development, according to Informa's BioMedTracker. Some treat the disease by keeping blood cells from sticking together, thereby preventing blockages and resulting damage. Eli Lilly & Co.’s oral platelet inhibitor Effient (prasugrel) is one of three drugs in Phase III. Emmaus Life Sciences Inc. plans to file its data for its oral, prescription-grade L-glutamine by the end of this year, after presenting positive results from a Phase III trial in 230 pediatric and adult patients. Mast Therapeutics Inc.’s Phase III intravenous small molecule MST-888 is being developed for acute use in patients with vasoocclusive crisis, to prevent re-hospitalization.

A number of companies, including Pfizer and Novartis, are developing injectable drugs that work against vascular adhesion molecules called selectins.

Gene therapies also hold potential – bluebird bio Inc.’s autologous, one-time, lentiviral vector treatment LentiGlobin BB305 is being tested in a very small Phase I/II study of beta-thalassemia and severe sickle cell disease.

The pipeline candidate most similar to GBT440 is Baxter’s oral Aes-103, picked up through the acquisition of AesRx LLC. It increases the affinity of hemoglobin cells to oxygen, thereby preventing the sickling of red blood cells. Although the two drugs work in similar ways, Global Blood says that GBT440 is more potent, with a longer half-life and easier administration. In Phase II, Aes-103 was given four times a day at the dose of 1 g (a total of 4 g a day). Global Blood has yet to determine the dose of GBT440, but animal studies suggest it will range from 80 mg to 250 mg per day.

The company believes that past experience with the oral immunomodulator tucaresol, which increases the binding of oxygen in hemoglobin, bodes well. In a small study published in 2003, the drug showed a benefit for correcting sickle cell anemia, which provides some support for the mechanism of action, though in the study, the particular candidate tested also caused fever, swelling of lymph nodes, and rash, putting an end to development in the indication.

In addition to the general risk of the unknown, GBT's execs had some particular safety concerns for GBT440. For example, they were concerned that binding of oxygen could be excessive, depriving tissues of oxygen, Love says. But animal studies proved that this was not a realistic concern because the amount of drug needed to achieve the desired effects was vastly lower than what it would take to impair oxygen delivery. “It clearly works based on every preclinical assay we’ve done and now we want to prove it works in living individuals with the disease,” Love says.