FX201

Why Gene Therapy for Osteoarthritis?

Osteoarthritis (OA) is a painful, progressive disease of the joints for which there is no cure. According to the U.S. Centers for Disease Control, OA affects more than 32.5 million adults in the U.S., and this number is expected to grow substantially in the years ahead as a result of aging, obesity and sports injuries.^1,2 While often dismissed as a normal part of aging, OA is, in fact, a serious disease associated with significant health consequences, as well as a range of disabilities, caused by chronic pain, structural damage, progressive loss of function and decreased mobility. As a result, OA significantly limits a person’s ability to self-manage other conditions, such as obesity, diabetes, and hypertension given that OA related pain is associated with reduced physical activity, which in turn is associated with increased all-cause mortality. In fact, U.S. adults with symptomatic knee OA were found to be 23% more likely to die prematurely than people free from OA independent of age, sex, and race.³

Recognizing OA can progress over years, Flexion believes a potentially optimal way to deliver an effective drug to an OA joint for long-term benefit is through a locally injected gene therapy that could enable durable expression of a therapeutic drug at the site of disease. This approach may help to address the challenges with systemically delivered (e.g., oral, subcutaneous, intravenous) therapies intended for local effects within the joint as well as therapies that are injected locally but are cleared from the joint space shortly after administration.

What is FX201?

FX201 is an investigational gene therapy which utilizes a helper-dependent adenovirus (HDAd) vector carrying a coding sequence for an anti-inflammatory protein called interleukin-1 receptor antagonist (IL-1Ra) under the control of an inflammation-responsive promoter. FX201 is injected directly into the joint space (also termed the intra-articular space) and is intended to deliver as-needed anti-inflammatory activity to joint tissues over the long-term, with the goal to improve outcomes for OA patients.

Inflammation is a known cause of pain, and chronic inflammation is believed to play a major role in the progression of OA.⁴ Based on preclinical data, Flexion believes a single injection of FX201 could potentially enable expression of IL-1Ra in an OA joint for at least a year. By persistently suppressing inflammation, FX201 holds the potential to reduce pain and improve function in OA patients, as well as potentially modify the disease.

Potential Advantages of the HDAd Vector

Nonclinical data suggest that HDAd has a ~10-fold higher transduction efficiency for some joint tissues compared to Adeno-associated virus (AAV), a more commonly used viral vector for other gene therapy approaches. Further, the delivery of FX201 directly into the joint may enable a potentially safe and effective dose for the treatment of OA that is thousands of times lower than viral vector gene therapies delivered by systemic routes of administration.

Importantly, FX201 features an inflammation-responsive promoter based on the transcription factor NF-kB, which we believe facilitates IL-1Ra expression when the joint is inflamed. This inflammation-responsive promoter mechanism may enable FX201 to deliver as-needed anti-inflammatory action in the OA joint, which is supported by nonclinical data.

Why IL-1Ra as the Transgene Protein for FX201 and Osteoarthritis?

In more than ten preclinical studies in OA, across species, with different models and delivered as both recombinant protein and via viral vectors, IL-1Ra has been shown to provide both symptomatic relief as well as slow structural progression of the disease.^5-15

Further supporting IL-1Ra as a potential strategy in OA is that in clinical trials IL-1Ra injected locally into the joint appeared to provide acute pain relief and functional improvement in patients.^16-19 However, these benefits waned quickly over time, which may be due to IL-1Ra having insufficient residence time in the joint to achieve durable efficacy.

Published clinical data from an exploratory analysis of the large cardiovascular outcomes trial by Novartis called CANTOS (NCT01327846) appear to support the hypothesis that durable IL-1 inhibition may result in a slowing of OA disease progression.²⁰

In CANTOS, more than 10,000 patients with a history of myocardial infarction and elevated levels of a systemic inflammation marker called high-sensitivity CRP, received injections of the anti-IL-1beta monoclonal antibody Canakinumab or placebo every 3 months for up to 5 years, to assess cardiovascular benefits.

As part of CANTOS, the number of total hip or knee replacements was captured, which provided an opportunity to explore the effects of an anti-IL-1 targeted therapy on incidence rates of total joint replacements. Shown in Figure Y is the cumulative incidence of total hip or knee replacements in all trial subjects who received canakinumab compared with placebo, which represents over 1,300 patients who had a history of OA at baseline.

Investigators found the combined incidence rates for joint replacement were 40% to 47% lower with canakinumab treatment than with placebo over an average follow-up of almost 4 years. The CANTOS trial used elevated high-sensitivity CRP levels as an entry criterion, and these exploratory data suggest there may be a population of OA patients with inflammation that could be responsive to durable IL-1 inhibition as a disease-modifying approach.

FX201 Nonclinical Efficacy and Safety Results

Pharmacology studies with the rat, mouse, and horse orthologues of FX201 showed symptomatic improvement and potential for disease modification. To support filing of an IND and entry into clinical development, Flexion conducted a robust nonclinical pharmacology and toxicology program with FX201.

Efficacy data supporting potential for disease modification in OA from a nonclinical model (rat ACL-tear) are shown in Figure Z. Two different doses of the rat equivalent of FX201 and vehicle were injected into a rat knee at 7 days after ACL-tear. On the left are example histology sections at 12 weeks after injury. With only vehicle, there is clear structural damage (black arrow showing cartilage fissure) and substantial subchondral bone remodeling (black asterisk). Full histopathology data for cartilage/bone are in the right panel, where scores returned to near normal levels with FX201 treatment.

Nonclinical safety data have shown that a single injection of FX201 into the joint was well-tolerated and had no significant biodistribution outside the target joint tissues at multiple time points after injection.

FX201 Clinical Development

In March 2020, Flexion treated the first knee OA patients with FX201 in a U.S. Phase 1 dose-escalation clinical trial (NCT04119687) to evaluate safety and tolerability, and capture assessments of potential clinical activity. This open-label trial was initially expected to enroll 15 to 24 patients and test three doses (low, mid and high dose) of FX201 in cohorts of 5 to 8 patients.

After completion of the low-dose and mid-dose cohorts and data review by an external Data Monitoring Committee, the high-dose cohort began enrollment. The trial was also expanded to enable up to an additional 20 patients to enroll in the low-dose and mid-dose cohorts. This expansion will enable the collection of additional safety and tolerability data as well as gather assessments of potential clinical activity in a larger number of knee OA patients. Flexion will also evaluate the biological activity of FX201 locally in the joint through several measures, including monitoring the presence of vector DNA and expression of FX201-driven IL-1Ra mRNA in synovial fluid.

---

References

1. https://www.cdc.gov/arthritis/basics/osteoarthritis.htm
2. Arthritis Care Res (Hoboken). 2016 May;68(5):574-80
3. Osteoarthritis Research Society International Arthritis: A Serious Disease. 2016; 3-21.
4. Robinson WH et al., Nat Rev Rheum 2016
5. Pelletier et al., Arth Rheum 1997; Watson-Levings et al., Mol Ther 2015
6. Zhang et al., Sc J Rheum 2011
7. Zhang et al., Sci Foundation 2011
8. Wang et al., Mol Ther 2016
9. Caron et al., Arth and Rheum 1996
10. Chen et al., Exp and Mol Med 2010
11. Elsaid et al., Osteo Cart 2015; Fernandes et al., Am J Path 1999
12. Frisbie et al., Gene Therapy 2002
13. Kimmerling et al., Eur Cell Mater 2015
14. Zhang et al., Scand J Rheum 2015
15. Watson Levings et al., Hum Gene Ther Clin Dev 2018
16. Chevalier et al., Arthritis Rheum 2009
17. Kraus et al., Osteoarthritis Cartilage 2012
18. Bacconnier et al., Ann Rheum Dis 2009
19. Scoville and Dickson, Ind J Rheum 2017
20. Schieker et al., Ann Intern Med 2020