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SPOTLIGHT

MD , MMS , Medical Director of the Boston Hemophilia Center and Assistant Professor of Pediatrics at Harvard Medical School , told ASH Clinical News . “ While there was a lot of anticipation of approval for a hemophilia gene therapy , I think the FDA conducted a careful review and made a prudent decision given this new therapeutic modality , the trends observed over time , and the small patient population with available data so far .”

As BioMarin continues gathering data in its singlearm phase III trial , other biotechnology companies are moving forward with alternative hemophilia gene therapies ( TABLE ). Pennsylvania-based Spark Therapeutics , which was acquired by Roche in December 2019 but continues to operate as an independent company , is evaluating its hemophilia A gene therapy , SPK-8011 , in a phase I / II trial . Pfizer and partner Sangamo Therapeutics also have a hemophilia A gene therapy in phase I / II testing and expect to begin a phase III trial by the end of 2020 . Yet another company , Georgia-based Expression Therapeutics , is planning to launch a phase I trial of its ex vivo gene therapy by year ’ s end .

Gene therapy development for hemophilia B has trailed behind that for hemophilia A , but uniQure and Pfizer both have hemophilia B candidates in phase III testing .

With several hemophilia gene therapies poised to enter late-stage clinical trials in the coming months , ASH Clinical News spoke with Dr . Croteau and other hemophilia experts involved in gene therapy development about the outstanding questions surrounding this therapeutic modality .

A One-Gene Target

As an X-linked recessive disorder , hemophilia predominantly occurs in males . There are approximately 30,000 people living with a form of hemophilia in the U . S ., and hemophilia A affects 1 in 5,000 male births every year , making it the most common form of the disease . ³ Patients with hemophilia typically lack one of two proteins necessary for the blood coagulation cascade : factor VIII ( FVIII ) in the case of hemophilia A and factor IX ( FIX ) in the case of hemophilia B .

FVIII is a co-factor within the clotting cascade , encoded by the F8 gene on the X chromosome and produced in sinusoidal endothelial cells in the liver and in endothelial cells outside the liver . FIX is a serine protease encoded by the F9 gene , which also is found on the X chromosome and is made by hepatocytes .

Standard treatment for hemophilia consists of replacing the missing coagulation factor through frequent intravenous ( IV ) infusions to treat current bleeding episodes or prevent future ones . Patients with severe hemophilia A ( those with FVIII levels ≤1 IU / dL ) may require multiple IV infusions per week , making a “ one-and-done ” gene therapy particularly attractive .

Hemophilia is amenable to gene therapy because both the A and B types are the result of a variant in a single gene . The gene therapy candidates under investigation are designed to provide long-term expression of the missing or abnormal coagulation factor at sufficient and steady enough levels to reduce – or even eliminate – the need for exogenous factor replacement . Several gene delivery vehicles have been tested , but the therapies in phase II or III development all use a recombinant adeno-associated virus ( rAAV ) vector with an inserted F8 or F9 gene . The therapy is administered as a one-time IV infusion , after which the vector is taken up by hepatocytes , where the synthesis of FVIII or FIX begins .

How Long Is “ Lifelong ?”

The appeal of hemophilia gene therapies is that they are a single-dose treatment that corrects the factor deficiency , rather than continuously replacing it . They are potentially curative , but whether they will really offer a “ cure ” depends on how long their effects last .

Paul Monahan , MD , Clinical and Translational Development Lead at Spark Therapeutics , noted that , “ because the AAV vector does not integrate into the host cell genome , and because the liver likely turns over about once a decade , the hemophilia field has yet to establish whether the FVIII expression will be lifelong .”

As of October 2020 , BioMarin ’ s valrox is the only gene therapy for hemophilia A that has reported interim phase III results . On the hemophilia B side , uniQure ’ s etranacogene dezaparvovec ( formerly AMT- 061 ) is in phase III testing , and a lead-in study to support a pivotal trial of Pfizer ’ s fidanacogene elaparvovec has completed enrollment . ^{4 , 5}

In the phase III BMN 270-301 trial , 16 patients who received valrox in the 6 × 10 ¹³ -vg/ kg dosing cohort had been followed for at least 26 weeks after infusion . ⁶ Their estimated median annual bleed rate ( ABR ) was 0 , and their estimated mean ABR was 1.5 , representing an 85 % reduction from baseline levels , when all patients were on standard-of-care FVIII replacement . Eight patients had FVIII levels of 40 IU / dL , on the highest end of the “ mild ” hemophilia A range , as assayed by the chromogenic substrate assay , which measures factor activity .

In January , researchers also reported 3-year data from the phase I / II trial of valrox , in which 15 men with severe hemophilia A received doses ranging from 6 × 10 ¹² vg / kg to 6 × 10 ¹³ vg / kg . ⁷ Patients in the highest dose cohorts maintained an ABR of less than 1 for 3 consecutive years and had significant decreases in the number of FVIII infusions required .

However , levels of FVIII appeared to fall 12 to 18 months after valrox infusion , which raised some concerns that a single gene therapy dose may not be enough to maintain protection from bleeding in the long term . Longer-term follow-up , including from the phase III trial , which the FDA requested in its CRL , should resolve this durability question .

Meanwhile , in 3-year follow-up data presented in July at the International Society on Thrombosis and Haemostasis ( ISTH ) 2020 Virtual Congress , Spark Therapeutics ’ SPK-8011 appeared to lead to safe and durable FVIII expression levels in men with severe hemophilia A . ⁸

Hemophilia A

The gene therapy uses Spark ’ s AAV-LK03 engineered vector , including a liver-specific promoter , to express the human F8 gene , explained the Hemophilia B trial ’ s principal investigator Lindsey George , MD , a physician at the Children ’ s Hospital of Philadelphia . A total of 14 trial participants received SPK- 8011 at one of three dose levels . Two patients lost FVIII expression following vector administration , but , among the remaining 12 patients who had sustained FVIII expression and were available for the preliminary efficacy analysis , Dr . George and colleagues observed “ a remarkable 91 % decrease in bleeding events .”

When investigators analyzed FVIII expression in the first 5 patients to receive vector , they found that the men in this group showed preliminary evidence of stable expression at follow-up between 2 and 3.3 years . Adverse events were generally mild and included elevations in liver enzymes .

“ The FVIII expression appeared to be stable and durable with SPK-8011 ,” Dr . George told ASH Clinical News . “ These are important data for the field because it shows that FVIII , which is not naturally made in the liver , can be expressed stably in hepatocytes with an AAV gene therapy vector .”

Spark is continuing its phase I / II to establish the optimal dose of SPK-8011 and to better understand how immunosuppressive steroids affect factor expression before starting a phase III trial , according to Dr . Monahan .

Giroctocogene fitelparvovec ( formerly SB-525 ), the product developed by Pfizer and Sangamo , is being investigated in the phase I / II Alta trial . As of June , the longest follow-up was 61 weeks . ⁹ Of the 5 men with severe hemophilia A who received the therapy at a dose of 3 × 10 ¹³ vg / kg , all had sustained FVIII activity levels , with a median of 64 % activity at 9 weeks post-infusion . One patient in this cohort had a grade 3 treatmentrelated serious adverse event of hypotension and grade 2 fever . Four participants received corticosteroids for elevated alanine aminotransferase levels , all of which fully resolved after treatment . The dose-ranging trial has a planned enrollment of 13 patients .

Pfizer also announced the pivotal phase III AFFINE trial , which is evaluating giroctocogene fitelparvovec in 63 patients with moderate to severe hemophilia A , enrolled the first patient in October 2020 .

Finding the Right Candidate

In addition to questions about the durability of gene therapies , there is also uncertainty about which patients are likely to derive the most benefit from this approach . Researchers are now looking for factors that influence gene therapy uptake and FVIII expression . “ Across all the hemophilia A gene therapy programs , it is fair to say that some individuals achieve quite good factor expression while others have much lower levels of expression ,” Dr . Monahan commented . “ We don ’ t

TABLE . Investigational Hemophilia Gene Therapies Sponsor Therapy Clinical Trial Stage

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