Two possibly curative gene therapies for the disease, which disproportionately affects Black people, are under consideration by the FDA.
Biologics license applications were filed recently for 2 potentially curative gene therapies in sickle cell disease (SCD), representing an astonishing advance for a condition characterized by crippling pain and a shortened life span even with current treatments.
“I couldn’t be more excited for the SCD community, because it’s long overdue,” said Terri Newman, PharmD, MS, an assistant professor of pharmacy and therapeutics at University of Pittsburgh School of Pharmacy, where she researches outcomes in SCD and barriers to treatment.
“This is a neglected disease, and we are years behind where we should be in terms of having treatment options for this population. But it’s a long road ahead to establish these gene therapy treatments as viable treatment options. We have to look at access (to current therapies) now,” she said.
Discovered in 1910, sickle cell disease is an inherited hemoglobin disorder that is characterized by red blood cells that take on a C-shape similar to a sickle instead of being round. The misshapen red blood cells stick together and clog blood vessels and starve the body of oxygen, which can lead to stroke, pain and organ damage, among other conditions.
Hydroxyurea, first used in SCD off-label in the 1980s and approved by the FDA for SCD in 1998, reduces sickling and raises the amount of fetal hemoglobin, increasing oxygenation. This versatile drug was a major breakthrough in SCD, which affects an estimated 100,000 individuals in the US, 90% of whom are Black. One percent of children with SCD die before the age of 3, according to the CDC.
Hydroxyurea was followed by other disease-modifying treatments (DMTs), including Endari (L-glutamine) in 2017, Oxbryta (voxelotor) in 2019 and Adakveo (crizanlizumab) in 2019. In August 2023, the European Commission followed the advice of an advisory committee and withdrew a conditional marketing approval for Adakveo in Europe, although it remains approved by the FDA.
Hydroxyurea is far and away the most frequently prescribed of the DMTs. Yet just 31% of patients with severe SCD are treated with DMTs, according to a recent study led by Newman, who says patients with SCD are chronically underserved by a medical community that is not adequately trained or focused on treating patients with this condition.
Resources for elucidating the nature of SCD and developing new treatments have tended to be less available than for other diseases, she says, a conclusion supported by other medical authorities.
“There’s disparate research funding. Cystic fibrosis has received much more funding than sickle cell disease, and providers have reported in surveys that they do not feel comfortable with managing care for this disease. Some of them rely on information they learned in residency. Some just don’t have the competency,” Newman said.
Severe SCD shortens the life of a patient by 30 years on average. It can involve frequent hospital stays, quick returns to hospital after treatment and regular blood transfusions. Disease outbreaks can be triggered by physical stress or oxygen-reduced environments, such as high altitudes or airplanes. Cases of post-traumatic stress disorder have been documented following the agony that sickling brings on.
Although currently policies lean toward limiting opioid prescriptions, the CDC has recommended an exception for individuals with SCD, “acknowledging the important role of opioids in pain management and the dangers of inadequate pain management,” according to the Institute for Clinical and Economic Review (ICER), which published in July 2023 a cost-effectiveness analysis of the SCD gene therapies.
Patients with SCD often find it challenging to obtain opioid prescriptions when needed because they may be stereotyped as addicts by inexperienced hospital staff.
For all these reasons, it is important to better align medical resources with the unmet need in SCD, Newman says. This should involve the development of comprehensive care centers that treat the whole disease with a multipronged approach involving diverse drug agents and specialists who know the full psychosocial-physical spectrum of SCD.
“Before, people didn’t make it into adulthood. There was more care and attention paid to the younger community. There was a lot of evidence-based medicine going toward improving outcomes in young people with sickle cell disease. But now we see that after the transition to adulthood, there are many gaps in care because there are not that many comprehensive care centers for adults. There’s fragmentation of care, not continuity of care.”
Although DMTs can meaningfully improve the quality of life for those with SCD, the 2 gene therapies under FDA review offer the potential of freeing patients from a lifetime of disease and its treatment.
Lovo-cel (lovotibeglogene autotemcel), from Bluebird Bio, works by inserting a correctly functioning hemoglobin gene into a patient’s stem cells, and exa-cel (exagamglogene autotemcel) developed by Vertex Pharmaceuticals and CRISPR Therapeutics, involves gene editing to increase fetal hemoglobin. The FDA has set decision dates in December 2023 for both treatments. In addition, exa-cell has a decision date in March 2024, as treatment for transfusion-dependent beta-thalassemia, a blood disorder that reduces production of red blood cells
One notable drawback of both treatments is that they require myeloablative conditioning (use of the chemotherapy busulfan) to create space for the reengineered cells to take root. This adds time to the treatment process and involves risks of infection. In clinical trials for both products, serious adverse events attributed to the chemotherapy “were not infrequent,” according to ICER.
In clinical trials, Bluebird Bio has fine-tuned the lovo-cel administration process. In results submitted to the FDA, 96.8% (31/32) of patients who received the adjusted administration experienced complete resolution of severe vaso-occlusive events (VOEs) during a 24-month follow-up. In recently reported results, 94.1% (16/17) of patients who received exa-cel were free of VOEs for at least 12 consecutive months.
Myeloablation with busulfan carries the risk of leukemia. Efforts are underway to develop a less toxic method. In July 2023, researchers at the University of Pennsylvania and Children’s Hospital of Philadelphia reported positive findings in the journal Science for a messenger RNA approach to gene therapy that does not require myeloablation.
Health care experts stress that the long-term durability of these treatments will not be known for many years. For now, however, stories are circulating of patients who, after a lifetime of restricted activity and pain, now have a relatively normal existence and lifestyle.
Neither company has disclosed their intended pricing, although ICER suggested that a price of $2 million per dose for either lovo-cel or exa-cel could be cost effective compared with standard of care. But the lower the price, the more patients with severe SCD could receive this treatment, ICER noted.
Patients with SCD do have the option for a hematopoietic stem cell transplant (HSCT), although only an estimated 14% of patients have access to appropriate donors. HSCT does have some risks, including organ toxicity, graft-vs-host disease, graft rejection, and mortality. HSCT is recommended only for younger patients with less-advanced disease damage.
Other options for managing SCD include screening adults and potential parents for the sickle cell trait, Newman said. Individuals are often unaware of their status, she notes. “There are efforts being made to have a nationwide screening program," said Newman. "There are people who find out only in later life they have sickle cell trait or sickle cell disease, so it’s important as part of the public health effort to make sure people are aware of their status, but also become educated about it, so they can be empowered to make decisions for themselves.”
Further, preimplantation genetic diagnostic (PGD) testing at the embryo stage of development also is available for SCD, enabling parents to combine PGD with in vitro fertilization (IVF) to avoid giving birth to children who bear this inherited disease. It is unclear whether payers, including Medicaid, which covers 42% of births in the United States, will cover PGD-IVF. There are also ethical concerns about preselecting children using this process. The President’s Council on Bioethics has concluded that in the context of preventing life-threatening diseases, these technologies are appropriate.
Tiba mbili za jeni za kuokoa ugonjwa huo, ambao huathiri watu weusi kwa kiasi kikubwa, zinachunguzwa na FDA. Maombi ya leseni ya dawa za kibiolojia yaliwasilishwa hivi karibuni kwa matibabu mawili ya jeni ya uwezekano wa kuponya ugonjwa wa seli ya sickle, ikionyesha maendeleo ya kushangaza kwa hali inayojulikana na maumivu ya kuumiza na muda mfupi wa maisha hata na matibabu ya sasa. "Hakuna kitu ambacho kinaweza kuwa na msisimko zaidi kwa jamii ya SCD, kwa sababu ni muda mrefu zaidi, ""alisema Terri Newman, PharmD, MS, profesa msaidizi wa dawa na matibabu katika Chuo Kikuu cha Pittsburgh Shule ya Dawa, ambapo yeye utafiti matokeo katika SCD na vizuizi kwa matibabu." <unk>Hii ni ugonjwa unaopuuzwa, na tuko miaka nyuma ya mahali tunapaswa kuwa katika suala la kuwa na chaguzi za matibabu kwa idadi hii ya watu. Lakini ni njia ndefu mbele ya kuanzisha matibabu haya ya tiba ya jeni kama chaguzi za matibabu inayofaa. Lazima tuangalie upatikanaji (wa matibabu ya sasa) sasa, "alisema. Ugonjwa wa seli za mviringo (Sickle cell disease) ni ugonjwa wa urithi wa hemoglobini unaoathiri chembe nyekundu za damu ambazo huchukua umbo la C kama mviringo badala ya kuwa mviringo. Chembe nyekundu za damu huunganishwa pamoja na kuziba mishipa ya damu na kuharibu oksijeni ya mwili, ambayo inaweza kusababisha kiharusi, maumivu na uharibifu wa viungo, kati ya hali nyingine. Hydroxyurea, ambayo ilitumiwa kwa mara ya kwanza katika SCD mnamo 1980, na kupitishwa na FDA kwa SCD mnamo 1998, hupunguza ugonjwa wa sickle na kuongeza kiasi cha hemoglobini ya kiinitete, na kuongeza oksijeni. Dawa hii ya dawa ya kulevya ilikuwa mafanikio makubwa katika SCD, ambayo huathiri takriban watu 100,000 nchini Marekani, 90% ya ambao ni weusi. Asilimia moja ya watoto walio na ugonjwa huo hufa kabla ya kufikia umri wa miaka mitatu, kulingana na CDC. Hydroxyurea ilifuatwa na matibabu mengine ya kubadilisha ugonjwa (DMT), pamoja na Endari (L-glutamine) mnamo 2017, Oxygen (Voxelator) mnamo 2019 na Advil (Crystallizumab) mnamo 2019. Katika Agosti 2023, Tume ya Ulaya ilifuata ushauri wa kamati ya ushauri na kuondoa idhini ya uuzaji ya masharti kwa Adapivir huko Ulaya, ingawa bado imeidhinishwa na FDA. Hydroxyurea ni moja ya dawa za kawaida zinazotumiwa na wagonjwa. Hata hivyo, asilimia 31 tu ya wagonjwa wenye ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa. """Vitu vya kueleza asili ya ugonjwa wa SCD na kuendeleza matibabu mapya vimekuwa chini ya kupatikana kuliko kwa magonjwa mengine,"" anasema, hitimisho linaloungwa mkono na mamlaka nyingine za matibabu." <unk>Kuna fedha za utafiti tofauti. Cystic fibrosis ni ugonjwa wa seli ya sickle, na wataalamu wa afya wanasema kuwa hawajui jinsi ya kuitunza. Baadhi yao hutegemea habari walizojifunza wakiwa wakazi. Baadhi tu hawana uwezo, "Newman alisema. Ugonjwa wa SCD unaopungua kwa kiwango kikubwa hufupisha maisha ya mgonjwa kwa wastani wa miaka 30. Inaweza kuhusisha kukaa hospitalini mara nyingi, kurudi haraka hospitalini baada ya matibabu na kutiwa damu mishipani kwa ukawaida. Matatizo ya magonjwa yanaweza kusababishwa na mkazo wa kimwili au mazingira yenye oksijeni kidogo, kama vile urefu mkubwa au ndege. Kisa cha ugonjwa wa mkazo baada ya majeraha vimeandikwa kufuatia maumivu makali ambayo ugonjwa huo huleta. "Hata kama sera za sasa zinaelekea kupunguza dawa za opioid, CDC imependekeza ubaguzi kwa watu wenye SCD, ""ikikubali jukumu muhimu la opioids katika usimamizi wa maumivu na hatari za usimamizi wa maumivu usiofaa,"" kulingana na Taasisi ya Mapitio ya Kliniki na Kiuchumi (ICER), ambayo ilichapisha Julai 2023 uchambuzi wa ufanisi wa gharama za matibabu ya jeni ya SCD." Wagonjwa wenye ugonjwa wa SCD mara nyingi hupata changamoto kupata dawa za opioid wakati zinahitajika kwa sababu wanaweza kuwa stereotyped kama addicts na wafanyakazi wa hospitali wasio na uzoefu. Kwa sababu hizi zote, ni muhimu kuunganisha vizuri rasilimali za matibabu na mahitaji yasiyotimizwa katika SCD, Newman anasema. Hii inapaswa kuhusisha maendeleo ya vituo vya huduma kamili ambavyo hutibu ugonjwa wote kwa mbinu ya pande nyingi inayohusisha mawakala wa dawa mbalimbali na wataalamu ambao wanajua wigo kamili wa kisaikolojia na kimwili wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa. Kabla ya hapo, watu hawakuweza kufikia umri wa watu wazima. Kulikuwa na uangalifu na uangalifu zaidi kwa jamii ya vijana. Utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti. Lakini sasa tunaona kwamba baada ya mabadiliko ya watu wazima, kuna mapungufu mengi katika huduma kwa sababu hakuna vituo vingi vya huduma kamili kwa watu wazima. "Hata ingawa DMT inaweza kuboresha ubora wa maisha kwa wale walio na SCD, matibabu mawili ya jeni chini ya ukaguzi wa FDA yanatoa uwezekano wa kuwaweka huru wagonjwa kutoka kwa maisha ya ugonjwa na matibabu yake. """ LOVO-CEL (lovoblogin autotemcel) kutoka Bluebird Bio inafanya kazi kwa kuingiza jeni la hemoglobini linalofanya kazi kwa usahihi katika seli za shina za mgonjwa, na exogam-cell (exogam-glogin autotemcel) iliyoundwa na Vertex Pharmaceuticals na CRISPR Therapeutics, inahusisha uhariri wa jeni ili kuongeza hemoglobini ya kiinitete. FDA imeweka tarehe ya uamuzi mnamo Desemba 2023 kwa matibabu yote mawili. "Kulingana na utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti wa utafiti.""" Hilo huongeza muda katika mchakato wa matibabu na huhusisha hatari ya maambukizo. Katika majaribio ya kliniki kwa bidhaa zote mbili, matukio mabaya makubwa yanayohusishwa na chemotherapy <unk>walikuwa si nadra,<unk> kulingana na ICER. Katika majaribio ya kliniki, Bluebird Bio imeboresha mchakato wa utoaji wa lovo-cell. Katika matokeo yaliyowasilishwa kwa FDA, asilimia 96.3 ya wagonjwa waliopokea matibabu yaliyorekebishwa walipata uharibifu kamili wa matukio mabaya ya vaso-occlusive (VOA) wakati wa ufuatiliaji wa miezi 24. Katika matokeo yaliyoripotiwa hivi karibuni, 94.1% (16% -17) ya wagonjwa waliopokea exaCell walikuwa huru kutoka kwa VOE kwa angalau miezi 12 mfululizo. Myeloablation na busulfan hubeba hatari ya leukemia. Jitihada zinafanywa ili kutengeneza njia isiyo na sumu sana. Katika Julai 2023, watafiti katika Chuo Kikuu cha Pennsylvania na Hospitali ya Watoto ya Philadelphia waliripoti matokeo mazuri katika jarida la Sayansi kwa mbinu ya RNA ya mjumbe kwa tiba ya jeni ambayo haihitaji myeloablation. Wataalamu wa afya wanasema kwamba matibabu hayo yatakuwa na matokeo mazuri kwa muda mrefu. Hata hivyo, kwa sasa, hadithi zinaenezwa za wagonjwa ambao, baada ya maisha ya shughuli zilizopunguzwa na maumivu, sasa wana maisha ya kawaida. Kampuni hiyo haijafunua bei ya dawa hiyo, ingawa ICER imedokeza kuwa bei ya dola milioni mbili kwa kipimo cha livo-cell au exocell inaweza kuwa na ufanisi wa gharama ikilinganishwa na kiwango cha huduma. Lakini bei inapoongezeka, wagonjwa wengi wenye ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa wa ugonjwa. Kwa wale walio na ugonjwa wa SCD, kuna uwezekano wa kupandikizwa kwa seli za msingi za hematopoietic (HSCT), ingawa inakadiriwa kuwa asilimia 14 tu ya wagonjwa wana uwezo wa kupata wafadhili wanaofaa. HSCT ina hatari kadhaa, ikiwa ni pamoja na sumu ya chombo, ugonjwa wa graft-vs-host, kukataliwa kwa graft, na vifo. HSCT inapendekezwa tu kwa wagonjwa wadogo wenye uharibifu wa ugonjwa usio na maendeleo. "Watu wengine wanaopaswa kufanya hivyo ni kuwachunguza watu wazima na wazazi wawezao kuwa wazazi wao ili kujua kama wana ugonjwa huo,"" alisema Newman." Yeye asema kwamba mara nyingi watu hawajui hali yao. "Kuna jitihada zinazofanywa za kuwa na programu ya uchunguzi wa kitaifa", alisema Newman. "Watu wengi wanajua kwamba wana ugonjwa wa seli ya mviringo, kwa hivyo ni muhimu kama sehemu ya juhudi za afya ya umma kuhakikisha watu wanajua hali yao, lakini pia kupata elimu juu yake, ili waweze kupewa nguvu ya kufanya maamuzi kwa wenyewe. ""Zaidi ya hayo, upimaji wa utambuzi wa maumbile (PGD) katika hatua ya maendeleo ya kiinitete pia inapatikana kwa SCD, kuwezesha wazazi kuchanganya PGD na IVF ili kuepuka kuzaa watoto ambao wana ugonjwa huu wa urithi." Kwa hivyo, haijulikani ikiwa wafadhili, pamoja na Medicaid, ambayo inashughulikia 42% ya kuzaliwa nchini Marekani, itafunika PGD-IVF. Pia kuna wasiwasi wa kimaadili kuhusu kuchagua watoto mapema kwa kutumia mchakato huu. Baraza la Rais juu ya Bioethics limefikia mkataa kwamba katika muktadha wa kuzuia magonjwa ya kutisha maisha, teknolojia hizi ni sahihi.