Advances in the Treatment of Rare Diseases

Why 2018 Will be a Breakthrough Year for These Rare Diseases

With Rare Disease Day upon us, we highlight critical advances in drug development expected in 2018

In the last several years, disease-modifying therapies (DMTs) have reached the clinic for a variety of devastating rare pediatric conditions such as spinal muscular atrophy (SMA) and cystic fibrosis (CF), which will transform the lives of these patients.

Although remarkable strides in treatment have been made for a handful of conditions, tremendous unmet need remains for the bulk of patients suffering from rare diseases.

As drug developers increasingly focus on drug development for rare diseases, the rate at which treatments for these conditions have become available has steadily increased:

Here, we highlight some of the key rare disease breakthroughs we expect to see in 2018:


Alnylam and Ionis will Battle for Dominance of the ATTR Amyloidosis Market

Key players: Pfizer, Ionis, Alnylam

Disease snapshot: Amyloidosis is characterized by toxic accumulation of aggregated, misfolded proteins in organs and tissues. Subtypes of amyloidosis are defined by the protein precursor involved, and include amyloid light chain (AL), amyloid A (AA), or amyloid transthyretin (ATTR) amyloidoses.

ATTR amyloidosis, a key current focus of drug developers, exists in two clinical subtypes, characterized by either wild-type or mutant transthyretin (TTR) protein accumulation.

Wild-type TTR deposits may stiffen and thicken the heart which, over time, leads to cardiomyopathy.

Patients with mutant TTR can develop polyneuropathy, cardiomyopathy, or both. Survival in ATTR amyloidosis varies widely, ranging from months to years depending on the TTR genotype and the severity of the resulting amyloid cardiomyopathy and/or polyneuropathy.

Current treatment and unmet need: Although TTR stabilizers (e.g., tafamidis [Pfizer’s Vyndaquel]) and amyloid degraders (e.g., doxycycline/tauroursodeoxycholic acid) may be prescribed to help maintain TTR structure and clear TTR amyloid deposited in the organs, physicians contend that more-efficacious therapies are needed. At present, only a liver transplant can eliminate the source of aggregating TTR protein.

Breakthrough: Breakthroughs appear on the horizon in the form of RNA translation-inhibiting therapies from Ionis (i.e., the antisense oligonucleotide inotersen) and Alnylam (i.e., the small interfering RNA patisiran).

FDA decisions on marketing applications for both agents are anticipated in Q3 2018. Inotersen and patisiran bind the TTR mRNA and suppress its expression, reducing the production of the corresponding protein.

The clinical results so far indicate that small interfering RNA and antisense oligonucleotides are potent approaches to reduce TTR protein production and significant improvements in modified neurological impairment score +7 (mNIS+7) were observed in the pivotal studies.

As of now, patisiran showed a difference of 34 points in mNIS+7 versus placebo, meaningfully higher than inotersen’s 20-point difference. In addition, patisiran showed fewer safety signals than inotersen, further strengthening the case for this agent.

Regardless of which therapeutic is preferred, the launch of these agents will surely be transformative for patients suffering from ATTR.


Shire’s Lanadelumab May Shift Managing Hereditary Angioedema from Treatment to Prevention

Key players: CSL Behring, Haegarda / Shire, Pharming Healthcare

Disease snapshot: Hereditary angioedema (HAE) is an autosomal-dominant genetic disorder caused by mutations in the gene coding for C1 inhibitor (C1-INH) protein.

The disease is characterized by recurrent swelling of subcutaneous or submucosal tissues resulting from elevated levels of the vasodilator bradykinin, a downstream effect of C1-INH abnormalities.

Acute HAE attacks affect various parts of the body including the face, larynx, hands, feet, and abdomen, and patients with HAE have an increased risk of disability and death.

Current treatment and unmet need: Plasma-derived C1-INH (CSL Behring’s Berinert and Haegarda and Shire’s Cinryze), icatibant (Shire’s Firazyr), ecallantide (Shire’s Kalbitor), and recombinant human C1-INH (Pharming Healthcare’s Ruconest) provide effective management of symptoms and collectively offer dosing flexibility to match patient preferences.

Interviewed experts report that timely access to these agents has greatly reduced visits and hospitalizations in HAE; however, they contend that prevention—rather than management—of symptoms would be preferable to reduce the development of future comorbidities.

Breakthrough: Shire’s lanadelumab (SHP643) is a fully human monoclonal antibody that specifically inhibits plasma kallikrein, which plays a key role in the development of angioedema.

Clinical data indicate that lanadelumab is highly efficacious in reducing HAE attack frequency, reducing the monthly attack rate by 87% with subcutaneous bi-weekly administration, which is a meaningful improvement upon the efficacy of currently available prophylactics (e.g. Cinryze) as well as a reduction in delivery burden over the first-generation C1-INH therapies that require frequent infusions of larger drug volumes.

Shire’s BLA for lanadelumab was accepted by the FDA in Feb. 2018, and an FDA ruling is set to arrive in Aug. 2018. The EMA granted Shire accelerated approval in Feb. 2018, possibly making lanadelumab available in Europe as early as Sept. 2018.

Lanadelumab is poised to be a superior option for HAE patients across nearly all clinical parameters, now it’s just a matter of getting it into their hands once the agent is approved.


Rigel’s Fostamatinib is Expected to Provide a Much-Needed Option for Immune (Idiopathic) Thrombocytopenic Purpura Patients

Key players: [Roche, Rigel]

Disease snapshot: Immune (Idiopathic) thrombocytopenic purpura (ITP) is a hematological disorder marked by the destruction and decreased production of platelets, which are the cells critical for blood coagulation.

Although ITP is considered an acquired autoimmune disorder, genetic inheritance is suspected to play a role in disease onset but has not yet been conclusively demonstrated.

ITP presents in either an acute form, with clinical symptoms persisting fewer than three months before resolving, or a chronic form, in which disease symptoms persist for longer than one year.

Current treatment and unmet need: Typically, acute ITP treatment is initiated with either glucocorticoids or intravenous immunoglobulin –two effective, longstanding mainstays of therapy.

Should these therapies prove unsuccessful and a patient’s ITP becomes chronic, physicians often turn to one of several second-line therapies, which may include thrombopoietin-receptor agonists (TPO-RAs) or the anti-CD20 agent rituximab (Roche’s Rituxan).

Splenectomy is another treatment option; however, its use has declined since the introduction of TPO-RAs.

There is unmet need for newer agents to improve platelet responses in patients.

Breakthrough: Rigel Pharmaceuticals’ fostamatinib is a selective oral inhibitor of the enzyme Syk, which has been tested in two Phase III trials in patients with persistent/chronic ITP.

Although fostamatinib delivered mixed results in the two pivotal studies, pooled analyses suggest the drug significantly increased the proportion of patients reaching a stable platelet response versus placebo.

Based on these promising clinical data, Rigel submitted an application for approval to the FDA in 2017, and a decision is expected in April 2018.


Primary Sclerosing Cholangitis Patients May Receive Some Life-Changing News from Gilead

Key players: [Intercept, Gilead]

Disease snapshot: Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are two distinct but related rare progressive cholestatic liver diseases in which damage to the bile ducts prevents bile efflux, leading to liver damage, cirrhosis, and, ultimately, liver failure.

Current treatment and unmet need: These diseases can be particularly pernicious; they are largely asymptomatic, and once symptoms are clinically evident the disease is likely in an advanced stage that is associated with more severe outcomes.

Further, diagnostic testing for these indications is difficult, as it involves invasive examinations (liver biopsy) that are subjective in nature. Although liver transplantation may effectively remedy both conditions, only PBC has approved pharmacological interventions, namely ursodeoxycholic acid (UDCA) and obeticholic acid (Intercept’s Ocaliva).

Additionally, UDCA has been evaluated in PSC patients in clinical studies, after long-term treatment the agent was deemed ineffective.

Breakthrough: Several promising new PSC therapies are on the horizon, including Ocaliva, which is an agonist of the nuclear hormone receptor FXR. Last year, Intercept presented the first ever positive data for a pharmacological intervention for PSC patients.

Gilead is also developing an FXR agonist (GS-9674) for PSC, and a readout from a Phase II study of that drug is expected in middle of 2018. Owing to its similar mechanism of action to Ocaliva, there is significant enthusiasm that Gilead’s FXR agonist will also prove effective in treating PSC. Indeed, Ocaliva has demonstrated positive results in Phase II trials for another hepatic indication, nonalcoholic steatohepatitis, widely considered one of the hottest indications of interest at present.

Together, these drugs bring hope to a group of patients for which life-changing, non-surgical therapeutics will revolutionize their care.


Vertex’s Emerging DMTs Will Breathe Life Back into Cystic Fibrosis Patients

Key players: [Vertex, Novartis, Roche]

Disease snapshot: Cystic Fibrosis (CF) is an autosomal recessive disease resulting from trafficking and/or functional mutations in the CFTR gene, which encodes a transmembrane chloride and bicarbonate transporter.

Disease manifestations include infection, airway blockage, and chronic inflammation in the lung, as well as diminished absorption of nutrients due to pancreatic insufficiency. Chronic pulmonary infections and acute lung exacerbations are the most common and severe symptoms of CF, and they contribute to mortality.

Current treatment and unmet need:  Improving airway function is critical to improving outcomes and increasing survival among CF patients, and is commonly achieved using inhaled antibiotics and mucolytic agents. Another treatment goal is to combat other major complications of CF, such pancreatic insufficiency, which is accomplished through use of pancreatic enzyme replacements.

The introduction of DMTs, namely Vertex Pharmaceuticals’ Kalydeco and Orkambi, has revolutionized CF treatment. Patients with certain specific CFTR defects now have therapeutic options that address the underlying cause of the disease.

It is worth noting that limited data are available to inform how Vertex’s agents will affect long-term survival of CF patients; however, it is clear that, in the near-term, interviewed experts consider these DMTs, particularly Kalydeco, to be transformative.

Breakthrough: Following Kalydeco and Orkambi, Vertex’s Symdeko (tezacaftor/ivacaftor and ivacaftor), the third disease-modifying therapy for CF, was approved by the FDA in February 2018.

Notably, Symdeko can treat a CF population that overlaps with Orkambi (i.e., two copies of the F508del mutation in the CFTR), but is also effective in a unique subset of patients (i.e., those who have at least one mutation in the CFTR that is responsive to tezacaftor/ivacaftor and a second mutation which may not respond to the combination).

Although the efficacy of Symdeko appears only slightly higher than that for Orkambi when comparing across separate clinical trials, clinical data suggest that Symdeko has fewer drug-drug interactions and will offer improved tolerability.

In other exciting news, Vertex has initiated a Phase III trial evaluating a triple regimen comprising the next-generation corrector VX-659 in combination with tezacaftor and ivacaftor.

According to Phase II data, triple combination regimens significantly improved lung function in previously underserved CF patients who have one F508del mutation and one minimal function mutation (F508del/min). These data are particularly striking as patients with the F508del/min mutation combination have thus far proven very difficult to treat with DMTs.

On the heels of this first Phase III triple regimen trial, Vertex is poised to initiate additional regimens into late-phase testing in patients with at least one F508del mutation, which collectively comprise more than 80% of the U.S. CF population.

Taken together, the approval of Symdeko signals a step forward in treating CF, with Vertex’s triple-therapy combinations poised to revolutionize treatment and expand access to life-changing medicines for CF patients.


BlueBird Bio’s LentiGlobin May Deliver on the Promise on Gene Therapy for Sickle Cell Disease and Beta Thalassemia

Key players: [Bluebird Bio]

Disease snapshot: Sickle cell disease (SCD) and beta thalassemia (BT) are hematological rare diseases in which defects in the β-globin gene result in an inability to form normal hemoglobin.

β-globin gene mutations lead to the formation of hemoglobin S in SCD patients that can distort red blood cells and cause vaso-occlusive crisis, while deficient levels of b-globin result in decreased levels of hemoglobin in BT patients resulting in chronic anemia.

Current treatment and unmet need: In the small percentage of SCD and BT patients with an HLA-matched sibling donor, hematopoietic stem cell transplant can be curative.

Although symptomatic therapies (e.g., prophylactic penicillin, analgesics), regular blood transfusions, and iron chelation therapy have reduced comorbidities and extended the lives of many patients, the high cost and inconvenience associated with the standard-of-care due to the need for frequent visits to healthcare providers leaves most patients in need of affordable, convenient, effective treatment options.

Breakthrough: Potentially-curative treatment options such as gene therapies are on the horizon, and as SCD and BT are both recessive monogenic disorders, they are ideal candidates for gene therapy where reintroduction of a correct copy of the defective gene could bring significant therapeutic benefit.

Bluebird Bio’s LentiGlobin is a gene therapy in development for both SCD and BT, consisting of a lentiviral vector in which a functional version of the human βA(T87Q)-globin gene has been inserted.

Administration of LentiGlobin is a complex, multi-step process involving the harvesting of CD34+ hematopoietic stem cells from a patient’s bone marrow and transduction of the harvested cells with LentiGlobin, followed by an ex vivo expansion of the transduced cells.

Patients must undergo myelosuppressive therapy with busulfan (Otsuka Pharmaceutical’s Busulfex) to prepare the bone marrow for re-engraftment of the LentiGlobin-transduced cells. Once expanded to sufficient levels, the transduced cells are reinfused into the patient via a central catheterization after which, in most cases, they re-engraft into the patient’s bone marrow.

Overall, the LentiGlobin procedure has two distinct attributes which make it an attractive therapeutic.

The first is a production of functional hemoglobin that provides a direct therapeutic benefit to either a SCD or BT patient.

The second is LentiGlobin carries a threonine to glutamine mutation at amino acid 87 in the adult β-globin that confers anti-sickling properties, a key benefit to SCD patients, and further serves as way to distinguish the hemoglobin produced by Lentiglobin – a highly useful feature in clinical trials due to the ability to separately analyze endogenous and exogenous hemoglobin.

Moreover, gene therapies such as LentiGlobin have the potential to offer patients long-term therapeutic benefit through only a single procedure, in contrast to other diseases where frequent treatments are required for therapeutic benefit, while negatively impacting the patient’s quality of life and raising hospital costs.

Although procedures associated with LentiGlobin administration may carry serious risks, particularly those associated with the required busulfan myeloablative conditioning, it offers a potential cure and a host of quality of life benefits for SCD and BT patients (e.g., elimination of transfusion burden, decreased hospitalizations) that could outweigh the risks of myeloablative conditioning.

Overall, the clinical data expected in 2018 will offer valuable insight into the risks and benefits of gene therapy that can be offered by gene therapies such as LentiGlobin. However, interim data from clinical trials suggest that LentiGlobin may offer some SCD and BT patients benefit over standard-of-care and sets the stage for a new era of potentially curative gene therapies.


While rare diseases may have been neglected historically, the above examples only underscore the progress driven by research and renewed interest in these indications which may make 2018 the most promising year for orphan indications yet.


Contact us for additional information on our comprehensive assessment of the ATTR AmyloidosisHereditary Angioedema, Immune (Idiopathic) Thrombocytopenic Purpura, Primary Biliary Cholangitis, Cystic Fibrosis, Sickle Cell Disease, and Beta Thalassemia treatment landscapes.




Contributors: Michael Breen: Senior Business Insights Analyst, Steve Trueman : Business Insights Analyst and Jia-Min Zhuo : Business Insights Analyst
Published on: 01 March, 2018