Editor's note: Last week, BioWorld Insight looked at 2015 drug approvals in blood disorders. In Part II, we examine emerging noncancer hematology treatments featured at ASH, including efforts to treat sickle cell disease and experimental gene therapy.

Word has trickled down from scientists to investors to patients that gene therapy may offer a potentially curative approach for crippling blood disorders, such as sickle cell disease (SCD) and hemophilia, that involve the mutation of a single gene. That growing awareness is leading to a wholesale effort to handicap the field of noncancer hematology agents and propelling heightened – some would say naïve – expectations to produce tomorrow's therapies today.

Gene therapy, which achieved its first regulatory success with EMA approval of Glybera (alipogene tiparvovec) and is witnessing rapid development in rare indications such as retinal disease and cystic fibrosis, remains largely at the proof-of-concept stage in blood disorders. As hundreds of presentations at last week's annual meeting of the American Society of Hematology (ASH) clearly attest, the field is heating up. However, many challenges remain before gene therapies in the hematology space are ready for prime time.

"Saying that the use of gene therapy for a disease with a single protein failure, like sickle cell or hemophilia, would be anything other than a complete game-changer in the lives of these patients is an understatement," said David Weinreich, head of global development for specialty medicine at Bayer Healthcare Pharmaceuticals Inc., of Whippany, N.J., a unit of Bayer AG, of Leverkusen, Germany. "The issues are whether we can get it to work and – if we can get it to work – whether we can get stable, normal protein expression."

Scientific literature suggests that only a small amount of protein – on the order of approximately 5 percent in individuals with hemophilia A, for example – is needed to prevent spontaneous bleeds, according to Weinreich. Gene therapy could achieve that balance.

"The hope is out there," he told BioWorld Insight. "But it's still early and there are a lot of technical hurdles to overcome. As with everything in medicine, science doesn't necessarily move in a linear fashion."

'It's way too premature to declare SCD dead'

High expectations can lead to great disappointment. In recent months, perhaps no gene therapy company has felt that sting more than Bluebird Bio Inc., which is advancing Lentiglobin BB305 in beta-thalassemia and severe SCD and has a preclinical multiple myeloma program, partnered with Celgene Corp., of Summit, N.J., targeting B-cell maturation antigen – among other pipeline candidates.

The Cambridge, Mass.-based company drew quick attention last month when ASH abstracts dropped. Bluebird data revealed that transfusion independence was achieved in patients with beta-thalassemia major with non-beta-zero (non-β0/β0) genotypes who were treated with BB305 and followed for at least six months in the Northstar and HGB-205 studies. However, varying degrees of transfusion reduction, and no transfusion independence, occurred in patients with the more challenging beta-zero (β0/β0) genotype. The prospect that Bluebird's highly touted gene therapy approach might not offer a cure across the entire beta-thalassemia patient population sent investors into a panic. (See BioWorld Today, Nov. 6, 2015.)

The company's shares (NASDAQ:BLUE) fell 22 percent on Nov. 5, closing at $70.36. Shares took another hit last week, slumping 37.5 percent on Dec. 7, to close at $52.25, a day after Bluebird reported data from the phase I study, HGB-206, evaluating BB305 in patients with severe SCD, which suggested that only one of three patients dosed in the study appeared to show benefit. (See BioWorld Today, Dec. 8, 2015.)

Bluebird shares reached a historic high of $197.35 on May 29, almost two years after the company raised $101 million in its IPO, pricing shares at $17 apiece. After its steady climb, the stock has fallen by nearly 70 percent over the past six months. (See BioWorld Today, June 20, 2013.)

Despite investor angst, the learning curve in gene therapy doesn't necessarily lead to failure. In his takeaway on ASH, Piper Jaffray analyst Joshua Schimmer conceded that "BLUE has come under pressure," but he maintained that "it is evident to us that with significant improvements in transfection efficiency, Lentiglobin is likely to produce a sufficient amount of T87Q to achieve permanent transfusion independence in β0/β0 patients. Our due diligence suggests drugs like stem regenin 1 and prostaglandin E2 may be used to boost transfection efficiency of [hematopoietic stem cells]."

Bluebird is testing small-molecule enhancers to improve the percentage of modified cells in Lentiglobin, and the initial data look promising, Schimmer said.

Bluebird's ASH data suggested "the need for further improvement in protocol, which may take 1+ year to gain additional color," added Jefferies analyst Gena Wang. And Lifesci Capital's Jerry Isaacson observed that, although Lentiglobin ultimately may not be curative in everyone, importantly, "all beta-thalassemia patients [are] showing some form of clinical benefit to date," with a good safety profile.

Maintaining an overweight rating on Bluebird's stock, J.P. Morgan analyst Cory Kasimov concluded, "The bottom line is we think it's way too premature to declare SCD dead (not to mention β0/β0 B-Thal); at the same time, we come away from ASH with increased confidence in non-β0/β0 B-Thal and intrigued by BLUE's oncology pipeline and increasing productivity of the platform."

Conventional approaches in sickle cell also advancing

Bluebird's foibles in SCD and beta-thalassemia drew quick comparisons to some of its competitors. Sangamo Biosciences Inc., of Richmond, Calif., and partner Biogen Inc., of Cambridge, Mass., offered an update on their gene-editing approach to knock out BCL11A, a regulator of the transcriptional switch from fetal to adult beta-globin expression, in hematopoietic stem cells that are isolated and then returned to the patient. When the $314 million deal was inked last year, Sangamo also raised the tantalizing prospect of curing patients with severe SCD or beta-thalassemia. (See BioWorld Today, Jan. 10, 2014.)

The companies reported preclinical data at ASH reviewing the rationale for targeting the BCL11A enhancer – ultimately, to increase the production of fetal hemoglobin – and confirmed they remain on track to file an investigational new drug (IND) application for beta-thalassemia major in the first half of 2016 and for SCD in the second half of the year.

"SGMO/BIIB showed that BCL11A enhancer could be efficiently modified by zinc finger protein without affecting the normal function of hematopoietic stem cells," Jefferies' Wang noted in a flash note following the ASH presentation. The companies also reported detailed analyses "showing that stem cells could be modified efficiently at clinical scale and the modification does not interfere with the differentiation of all lineages from modified stem cells. Moreover, the up-regulation of fetal hemoglobin was shown to be comparable with knockout of BCL11A coding gene."

Some companies are working on more conventional approaches to treat SCD. Among those, Global Blood Therapeutics Inc. (GBT), of South San Francisco, gained traction quickly after launching in 2012 from Third Rock Ventures LLC with a $40.7 million series A. The company raised $120 million in August in its IPO, pricing shares at $20 apiece. (See BioWorld Today, June 14, 2012.)

At ASH, GBT reported data from an ongoing phase I/II trial showing that its SCD candidate, GBT440, inhibited polymerization of sickle hemoglobin, increased hemoglobin concentration, reduced red blood cell damage, improved oxygen delivery and reduced inflammation. The results included data from 30 patients with SCD who completed 28 days of treatment on GBT440 or placebo, expanding the safety and efficacy database previously reported in an initial cohort of eight patients.

Like Bluebird, GBT received a chilly reception on its ASH data. The company's shares (NASDAQ:GBT) fell more than 25 percent, to close at $33.93, on Dec. 7, following its oral ASH presentation and investor webcast. In his ASH notes, Lifesci's Isaacson observed that, "although overall effective in increasing hemoglobin levels in patients with sickle cell disease at [the] 28-day time frame, long-term durability of GBT440 may be a potential issue."

Mast Therapeutics Inc., of San Diego, offered data at ASH showing that its lead candidate, vepoloxamer, resulted in statistically significant reductions in the number of adherent sickle red blood cells to immobilized vascular cell adhesion molecule and reductions in hemolysis in blood from SCD patients (n=12). The company also presented preclinical data suggesting that vepoloxamer preserved platelet function under extended storage conditions and prevented exposure of phosphatidyl serine, a marker of platelet damage, in blood samples from patients with SCD.

Earlier this year, Mast initiated an open-label extension study to evaluate repeat dosing of vepoloxamer in patients who completed the phase III EPIC trial and were hospitalized for a subsequent vaso-occlusive crisis. (See BioWorld Today, May 27, 2015.)

In all, ASH featured more than 250 sessions on up-and-coming therapies in SCD and beta-thalassemia. More than three dozen candidates are being advanced by biotechs and big pharma, according to Cortellis Competitive Intelligence, though most remain in discovery. Among those in or nearing the clinic are luspatercept, from Acceleron Pharma Inc. and partner Celgene Corp.; rivipansel (GMI-1070), from Glycomimetics Inc. and partner Pfizer Inc., which also has PF-04447943; BAX-555 from Baxalta Inc.; Emmaus Medical Inc.'s L-glutamine; Sel-G1 from Selexys Pharmaceuticals Corp.; and HQK-1001 from Hemaquest Pharmaceuticals Inc. (See BioWorld Today, Aug. 4, 2011, Jan. 24, 2014, Oct. 12, 2011, Oct. 12, 2012, and March 13, 2012.)

New entrants continue to emerge. This month, Hillhurst Biopharmaceuticals Inc., of San Diego, landed a phase I Small Business Innovation Research grant from the National Institute of Neurological Diseases and Stroke to continue preclinical development of its lead product, HBI-002, which is designed to augment the cellular heme oxygenase metabolic pathway to limit inflammation and prevent apoptosis and oxidative injury. The company expects to file an IND next year to evaluate the oral therapy in conditions associated with inflammation and apoptosis, including SCD and acute cerebral injury.

'First couple of doses have to do the trick'

The same challenges that dog SCD and beta-thalassemia apply to the next generation of therapies to treat bleeding disorders such as hemophilia A and B. Despite recent drug approvals in the space – beginning last year with Biogen's Alprolix (coagulation factor IX [recombinant], Fc fusion protein) in hemophilia B and Eloctate (antihemophilic factor [recombinant], Fc fusion protein) in hemophilia A – companies are looking to gene therapy as a transformative approach, though they're less inclined to predict lifetime cures. (See BioWorld Today, June 10, 2014.)

Unsurprisingly, the larger hemophilia space has attracted a broader range of players, including Uniqure. In 2013, the Amsterdam-based company inked a €31 million (US$39.6 million) commercialization and equity deal with Chiesi Famaceutici SpA, of Parma, Italy, involving European and Chinese rights to Glybera and rights in Europe and several other territories to its hemophilia B gene therapy program, now in a phase I/II program, according to Cortellis. (See BioWorld Today, July 10, 2013.)

Glybera, approved in 2012 to treat lipoprotein lipase deficiency after its fourth round with the EMA, went through more than two years of negotiations with payers before the first patient was treated commercially this year – hinting at yet another looming challenge for gene therapy companies. (See BioWorld Today, Nov. 5, 2012, and March 5, 2015.)

Big pharma also has a major investment in the space, directly or with biotech partners. Bayer, which markets Kogenate FS (recombinant factor VIII) for hemophilia A, has advanced Kovaltry (BAY 81-8973) to filings in Europe, the U.S. and elsewhere as its follow-on treatment in adults and children with hemophilia A. But the pharma is clearly bullish on prospects for gene therapy. Last year, Bayer partnered with Dimension Therapeutics Inc., of Cambridge, Mass., in a potential $252 million deal focused on Dimension's adeno-associated virus (AAV) gene therapy. The technology was gained through partnerships with Regenx Biosciences LLC, of Washington, and the University of Pennsylvania, providing Dimension with exclusive gene therapy intellectual property and preferred access to multiple AAV vectors. (See BioWorld Today, June 24, 2014.)

The companies are advancing the preclinical factor VIII agonist, known as DTX201, in hemophilia A. Dimension also is developing DTX101, a factor IX (FIX) gene therapy candidate, to treat adults with moderate to severe hemophilia B and is expected to begin a phase I/II study by year-end.

At the highest level, the main distinction in gene therapy efforts is whether to apply gene editing or gene insertion techniques, Bayer's Weinreich observed.

"The scientific community has actually learned quite a bit on how viruses deliver genetic payloads into cells," he said. "The key is to get the protein where it belongs and to get it stably inserted."

The body is quick to recognize a virus used as a delivery system as an interloper and to mount a vigorous immune response. Gene therapy developers work under the premise that they can only sneak in several doses undetected, "which means that those first couple of doses have to do the trick," Weinreich said. "And the gene must be inserted stably so that the body starts producing a functioning version of that protein over time."

In the case of hemophilia, for instance, gene therapy offers little value if the gene "turns off" after six weeks and the patient once again requires traditional factor replacement.

"It's probably unlikely that you're going to get patients off factor replacement forever," Weinreich admitted, if for no other reason than normal cell replacement rate. "But is that curve one year? Five years? Ten years? We have no idea."

By the same token, if hemophilia patients could stop conventional therapy for 10 years after a few doses of a gene-modifying virus, "that would be a win," he added. "Is five years a huge advance? Probably. But it's a little more debatable when you get down to lower numbers."

'a series of challenges that have to be overcome'

Also in the hunt is Spark Therapeutics Inc., of Philadelphia, partnered with New York-based Pfizer in an effort to treat hemophilia B. Last week, Spark earned its first $15 million milestone payment as part of the potential $280 million deal to develop and commercialize SPK-FIX, designed to deliver a high-activity FIX gene to patients. Spark is running a U.S. phase I/II trial that is currently recruiting patients, according to Cortellis. (See BioWorld Today, Dec. 9, 2014.)

For Pfizer, the payoff would be a successor to its FIX therapy, Benefix, considered a standard-of-care treatment in hemophilia B.

The pipeline at Alnylam Pharmaceuticals Inc., of Cambridge, Mass., features fitusiran (ALN-AT3), an RNAi therapeutic designed to treat hemophilia and other rare bleeding disorders that was the topic of several presentations at ASH. Earlier this year, company researchers published preclinical data showing the therapy restored the balance in the coagulation cascade by increasing levels of the clotting factor thrombin. (See BioWorld Today, April 14, 2015.)

ALN-AT3 targets the enzyme antithrombin, which interferes with the pro-clotting protein thrombin, using siRNA connected to a targeting ligand that delivers the drug to liver cells. Alnylam plans to advance fitusiran into pivotal studies in mid-2016 following positive findings in a recently completed phase I trial.

Baxalta Inc., of Bannockburn, Ill., which saw recent FDA nods for its long-acting Adynovate (antihemophilic factor [recombinant], pegylated) in hemophilia A and Vonvendi (von Willebrand factor [recombinant]) in von Willebrand disease, is looking to an AAV8-based gene therapy technology as its next approach in hemophilia. (See BioWorld Today, Nov. 17, 2015, and Dec. 10, 2015.)

BAX 335 encodes a variant factor IX transgene with a transthyretin enhancer-promoter that increases hepatic transgene expression. Last year, before the split from Baxter International Inc., the company acquired the assets of Chatham Therapeutics LLC in a $70 million deal plus potential development, regulatory and commercial milestone payments. The move gave Baxter full access to Chatham's gene therapy platform, including a hemophilia B FIX program that was part of a 2012 collaboration between the companies. (See BioWorld Today, April 3, 2014.)

The move came just a week after Baxter, of Deerfield, Ill., said it planned to separate the development and commercialization of biopharmaceuticals and medical products into distinct companies, with the spin-out to maintain its focus on the global hemophilia market. (See BioWorld Today, March 28, 2014.)

The 2012 deal allowed Baxter to evaluate Chatham's Biological Nano Particle, or BNP, platform that served as the foundation of the AAV8-based gene technology. Baxter picked up global rights to market and commercialize the treatment, paying $25 million up front to advance the program through early trials, with the idea of integrating the technology into its development of BAX 335.

"The endgame for us – what we're driving toward and investing in – is gene therapy" to treat both hemophilia A and B, said Brian Goff, Baxalta's executive vice president and president of Baxalta Hematology. The company presented updated data on BAX 335 at ASH.

"We now have our own evidence to show that, particularly in the case of hemophilia B, we can get patients to a significantly elevated factor trough level" on a sustained basis, Goff told BioWorld Insight. One patient in the hemophilia B program has achieved more than 20 percent expression levels for more than a year.

"It's not a cure, but it's as close to a cure as many are likely to get to in our lifetime," Goff said.

The "common denominator" in Baxalta's approach to hemophilia therapies is direct factor replacement, according to Goff, "at a young enough age that there is very little, if any, joint damage and on a preventive basis."

Despite the global excitement about gene therapy, ongoing challenges include the selection of the delivery mechanism, or vector; the construct, or gene cassette; and the structure and design of the capsid, Goff said, along with a company's manufacturing capabilities.

For BAX 335 in hemophilia B, "we think in terms of 2020 as the target" for potential commercialization, he added. Hemophilia A, "which is technologically more complicated because it's a larger protein," could come along two to three years later, Goff predicted.

Bayer's Weinreich agreed that the science of gene therapy is advancing quickly, even if the timetable remains elusive.

"There are a series of challenges that have to be overcome, and it's going to take time," he said. "But if you want to be a leader in the hemophilia space, you have to participate in these kinds of disruptive and potentially life-altering therapies even while you continue to work on step-wise improvement of what's currently available."

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