• Sat. Sep 25th, 2021

Duchenne Muscular Dystrophy Market: What’s More Beyond Exon-Skipping Therapies?

ByASNF

Aug 27, 2021

Duchenne muscular dystrophy (DMD) is a rare genetic disorder usually diagnosed in young boys, gradually weakening muscles across the body until the heart or lungs fail. Symptoms often show up by the age of 5; as the disease progresses, patients tend to lose the ability to walk around the age of 12. As per a recent analysis by DelveInsight, DMD market is expected to achieve more than 8,000 million in revenue in the 7 Major Market (The United States, Germany, France, Italy, Spain, UK, and Japan) by the year 2030, owing to the launch of recent exon-skipping therapies along with expected approvals of the emerging therapies.

What are the currently available treatment options for patients with Duchenne Muscular Dystrophy (DMD)?

Currently, Sarepta is leading the DMD market with a strong, extensive pipeline and three approved antisense oligonucleotide products, namely Exondys 51 (eteplirsen) approved in September 2016, Vyondys 53 (golodirsen), and recently approved Amondys 45 (casimersen). These products target patients with a mutation to exon 51, exon 53, and exon 45, respectively. All approved in the past few years in combination can treat ~30% of all DMD cases. 

Vyondys 53 was approved in December 2019 for the patients with exon 53 skipping in the US. It is a major competitor for Viltepso (viltolarsen) approved in 2020 in the US and Japan. Viltepso is being developed and marketed by NS Pharma. The company further plans for EU approval of the drug; however, the Phase III trial for the EU locations is still recruiting, and the approval might depend on the further data readouts. Even though both the drugs offer the intravenous mode of administration, the former offered a mean dystrophin level with an increase of 0.88%, while the latter offered an increase of 1.9 % in their respective clinical trials. While the former was evaluated on a patient pool of 58 DMD patients, the latter was investigated in a trial size of eight DMD patients. Moreover, Viltepso is the only drug approved in Japan for DMD patients. Thus, it is expected to dominate the Japanese market. 

Another key player, PTC Therapeutics, has two approved products. Translarna (ataluren) has been approved to treat patients aged 2 years and older with Ambulatory DMD patients by (European Economic Area) EEA in 2014 with a negative response from the US FDA in 2017 pertaining to the efficacy of the drug. However, as per the latest news in 2021, the company plans to re-submit an NDA to the FDA based on the Translarna dystrophin study. The opinion of the US FDA with regard to the approval is much anticipated. Additionally, PTC is also planning to expand its EMA label to include Ambulatory patients as well. Another drug by PTC, Emflaza (deflazacort), targets all DMD patients aged 5 years and older. The drug was approved in 2017 in the US and is potentially superior as compared to conventional corticosteroids such as prednisone and prednisolone. Although the drug has faced major setbacks due to its extremely high cost of therapy in the United States, in the case of Europe, emflaza has been available for more than a decade at a much lower price.

What are the major challenges faced by the approved drugs?

It is worth noticing that all the approved products received accelerated approval, and further data is required for continued approval of all the drugs. Additionally, considering the historical trend in DMD, the probability of success to enter the market varies throughout 7MM. Interestingly the DMD market is quite disparate geographically in terms of regulatory approval (i.e., EMA versus FDA), with several instances of products being approved in one jurisdiction and rejected in the other based on the same clinical data. Thus, the current therapies are facing a major challenge for approval in the regions outside their respective pre-approved countries. For instance, Translarna, which is approved in EEA, met principal concerns for the US approval, whereas none of Sarepta’s exon-skipping therapies have to date received approval outside the United States.

Scope of upcoming therapies

The current scenario is anticipated to shift toward the upcoming therapies with fair competition between the approved and emerging therapies, as some of the emerging therapies are targeting the patient pool captured by the already existing drugs. Here is a list of major key players and competitors.

Upcoming therapies Emerging key players and major competitors
SRP-5051 (Sarepta) SRP-5051 is another drug in development by Sarepta for people with DMD who are amenable to exon 51 skipping. According to the analysis, results from Part A of the study found that the 30 mg/kg monthly dose resulted in eight times the dystrophin production at 3 months compared to Exondys 51, which was dosed weekly for 6 months. Treatment with this dose also led to 18 times the exon skipping at this time point. Considering that Sarepta’s SRP-5051 is a potentially more effective therapy, we expect it to replace Exondys 51 once it gets launched at less frequent doses by the year 2023, as per our estimates.
DS-5141b (Daiichi Sankyo) Daiichi is developing another exon-skipping therapy, DS-5141b, an exon 45 skipping therapy offering a subcutaneous route of administration and is being studied in a Phase I/II clinical trial conducted in Japan only. We anticipate that the drug may enter the Japanese market by 2024. Daiichi’s drug is expected to be a major competitor to Sarepta’s Amondys 45 in terms of the same target patient pool, although we are skeptical about the launch of Sarepta’s drug in Japan. However, we expect Daiichi’s drug to face competition when launched in the United States. Considering that the drug is in the early Phase of development, we still await further high phase trial results to evaluate and make a head-to-head comparison of the two drugs. 
PF-06939926 (Pfizer),SRP-9001 (Sarepta),SGT-001 (Solid Biosciences) After almost 15 years since the first gene therapy trial for Duchenne muscular dystrophy (DMD) began, the dream of a DMD gene therapy might turn into a reality, though with a lot of hurdles. There are currently three companies with competitive trials in the US: Solid Biosciences, Sarepta Therapeutics, and Pfizer. Considering the recent failure of Sarepta’s Phase III gene therapy trial, Pfizer’s PF-06939926 is in Phase III for 4–7 age ambulatory DMD patients with a potential first-mover advantage in the market. Sarepta’s gene therapy SRP-9001 is being developed for 4–17 years ambulatory children and non-ambulatory adolescents on stable corticosteroids. Phase II (Study 102) study for SRP-9001 demonstrated topline results; however, the primary functional endpoint of change in the North Star Ambulatory Assessment (NSAA) total score was not met. It is now believed that the positive finding and the manageable tolerability data from a Phase II study will guide it to a better Phase III design.Whereas Solid Biosciences is developing SGT-001 for 4 years and older ambulatory and non-ambulatory patients in a Phase I/II trial. The company faced a clinical hold on the IGNITE-DMD trial, which was eventually lifted by the US FDA in October 2020. The preliminary results reported by the company showed a decrease in creatine kinase levels and improvements in NSAA and PODCI. Conclusively, considering recent unsatisfactory results by gene therapies such as SRP-9001 and severe adverse effects of Pfizer’s gene therapy, we are not very optimistic about the gene therapies share in the DMD market and have assumed their entry with a low probability of success.
Vamorolone (Reveragen + Santhera) DelveInsight believes that Vamorolone, which is being developed for 4–7 year’s ambulatory patients in a Phase II trial, will capture a major chunk of the market during the forecast period, considering the large patient pool it is targeting. The drug is a dissociative steroid that works similar to other corticosteroids by activating certain pathways within the cell and inhibiting others. It received Orphan Drug designation in the US and Europe, plus Fast Track and Rare Pediatric Disease designations in the US. It has also received the Promising Innovative Medicine designation in the UK. The drug demonstrated highly effective and safe data from the ongoing study and we are looking forward for early approval of Vamorolone, as the company is planning for an NDA filing based on the current Phase IIb trial.
Givinostat (Italfarmaco), TAS-205 (Taiho Pharma) Italfarmaco’s Givinostat, an orally available histone deacetylase inhibitor (HDAC) is being evaluated in a phase III stage of development for DMD. In October 2020, the US FDA granted a Rare Pediatric Disease designation to the drug. Earlier, the company also received an Orphan Drug designation and Fast Track designation from the FDA.  In June 2021, Italfarmaco announced topline data from its proof-of-concept phase II trial with Givinostat and is now running a Phase III trial for an estimated approval in the year 2023. TAS-205 is a selective hematopoietic prostaglandin D synthase (HPGDS) inhibitor discovered by Taiho Pharmaceutical. Currently, the drug is being investigated in phase III clinical developmental trial for the treatment of DMD patients in Japan, therefore we expect the drug to get approval in Japan first. Both Givinostat and TAS-205, are being evaluated in Ambulatory DMD Patients.
Pamrevlumab (Fibrogen) The major driving force for Pamrevlumab is the increase in cardiac function, grip strength, and preservation of muscle function offered by the drug. Therefore, with the additional benefit of increasing these key problems faced by DMD patients, the drug is believed to be a potential market player during the forecast period. The drug targets both non-Ambulatory (12 years and older) and ambulatory (6–11 years) DMD patients.
CAP-1002 (Capricor),ATL1102 (Antisense) CAP-1002 is a cell therapy targeting improvement in the upper limb function, cardiac function, pulmonary function, and other endpoints. It is expected to compete to some extent with ATL1102 as Antisense is also targeting improvement in upper limb function. It is estimated that ATL1102 has significant potential to capture the non-ambulatory patient pool, given the low level of competition. Additionally, ATL1102 reported highly promising Phase II trial results. The current standard of care for non-ambulatory patients is long-term corticosteroid use which is associated with significant side effects. Thus, it is believed that the drug has a great growth opportunity to capture a large patient share of the non-ambulant DMD market. Furthermore, it is anticipated that the drug will launch in EU5 prior to its launch in the US, given the feedback on the Paediatric Investigation Plan (PIP) for the development of the drug from the Paediatric Committee (PDCO) of the EMA. The drug is also expected to reduce the usage of corticosteroids.

Overcoming the Cost burden among DMD patients

Patients with DMD face a severe challenge in combating the high price associated with the approved therapies. In 2017, Marathon Pharmaceuticals agreed to sell its newly approved steroidal treatment– Emflaza, to PTC, offloading the drug after backlash over initial plans to charge a list price of USD 89,000 per year. PTC cut down to around USD 35,000 per year for a child weighing 25 kg but later increased the drug’s list price by about 9%, to more than USD 65,000 annually. This high price makes this old-turned-new drug a significant cost burden for DMD patients. Through the PTC Care Assistance Program, PTC therapeutics provides financial assistance for DMD patients who are prescribed Emflaza. Moreover, for patients who have commercial insurance and have out-of-pocket costs associated with Emflaza and who qualify for assistance, PTC Cares offers a co-pay assistance program. Additionally, the Bridge Program allows patients currently taking Emflaza to continue receiving it free of charge while waiting for insurance verification of coverage. 

To make the drugs (Exondys 51, Vyondys 53, and Amondys 45) easily available and affordable to the patients, the company (Sarepta) has a patient support program called SareptAssist, designed to help patients navigate the process of starting and staying on these drugs. The company also has a Sarepta Patient Co-Pay Assistance Program which was created for eligible individuals with commercial health insurance in the US who are prescribed these therapies. This program may help with some out-of-pocket costs related to receiving treatment, such as co-pays, co-insurance, and deductibles. Similarly, the only DMD drug approved in Japan – Nippon Shinyaku’s Viltepso-offers services and resources to patients through the NS Support program

Thus, it is believed that the emerging drugs may face a significant challenge to reimburse their key products for better patient compliance. Certain DMD drugs under development have received Orphan Drug status by the FDA and EMA, providing certain benefits for approvals and reimbursements over other drugs. This, in turn, might boost the accessibility of these drugs.

Increase in New Born Screening, research, and awareness

A significant problem faced by DMD patients is the side effect associated with Steroids – the current standard of care. DelveInsight anticipates that the upcoming therapies can combat the current unmet need and the big stink faced by DMD patients. In July 2021, CureDuchenne teamed up with Brigham and Women’s Hospital, US, to launch the first free newborn screening initiative for DMD in the US. The partnership established Brigham and Women’s Hospital as the only US birth hospital to offer parents the choice of screening their new baby for DMD. An increase in newborn screening and awareness for the disease is anticipated to drive the increasing DMD patient pool.

Additionally, early testing would allow the families to access treatments that may help delay or prevent symptom onset and improve outcomes. Moreover, correct diagnosis also can give parents and caregivers a better understanding of how a child’s disease is likely to progress. Thus, an increase in research and developmentawareness and newborn screening are further expected to boost the diagnosis and treatment for this patient pool.

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